Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
This variantScenario
BenignPathogenic
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
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About BRCA2
BRCA2 encodes a DNA repair protein that maintains genome stability by repairing double-strand breaks through homologous recombination and by protecting DNA replication forks. It acts as a tumor suppressor, and inherited loss-of-function changes cause hereditary breast and ovarian cancer syndrome, with elevated lifetime risks of breast, ovarian, prostate, and pancreatic cancers; biallelic changes cause Fanconi anemia complementation group D1. Reduced or altered BRCA2 activity is implicated in multiple tumor types, and PARP inhibitors are an approved treatment for BRCA2-associated ovarian and breast cancers.
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Criteria may be applied incorrectly, sources may be misread, and a
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Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen BRCA2 VCEP v1.2. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at very strong: the BRCA2 exon 14 frameshift PTC p.(Tyr2383SerfsTer11) is pre-assigned PVS1 by ENIGMA Table 4 and lies before the c.9600 NMD boundary.
PM5Strong
PM5 · strong
Met at Strong: ENIGMA Table 4 pre-assigns PM5_Strong (PTC) to BRCA2 exon 14 protein-termination variants, and this frameshift's stop codon falls in exon 14.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
Pathogenic: PVS1 (very strong) plus PM5 (strong) satisfy the ENIGMA BRCA2 VCEP Table 3 combination rule.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 6 not met · 5 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Governing framework: the ClinGen ENIGMA BRCA1 and BRCA2 VCEP specification v1.2 applies to BRCA2 (NM_000059.4), so generic ACMG/AMP fallback was not used for any of the three criteria in this group.
PVS1: met at full weight (very strong). c.7141_7147dup is an exon-14 frameshift whose PTC (codon 2393, ~c.7177) falls in the same exon 14 (c.7008-c.7435). Specifications Table 4 pre-assigns PVS1 (full weight) to BRCA2 exon-14 PTC variants, and the ENIGMA BRCA2 PVS1 decision tree (Appendix D, Figure 5) predicts NMD for PTCs 5' of c.9600, so no NMD-escape downgrade applies. The truncation removes the DNA-binding domain and both C-terminal nuclear localization signals.
PM4: not applicable. The ENIGMA BRCA2 v1.2 framework specifies 'Do not use' for PM4 (folded into the PP3/BP4 bioinformatic pathway), and the variant is an out-of-frame frameshift rather than an in-frame protein length change or stop-loss.
BP3: not applicable. The ENIGMA BRCA2 v1.2 framework specifies 'Do not use' for BP3 (captured by bioinformatic tool prediction and domain analysis), and the variant is not an in-frame deletion/insertion in a repetitive region.
Consequence-level summary: this is a classic BRCA2 truncating (loss-of-function) allele; the only consequence-of-loss-of-function criterion the BRCA2 VCEP permits here is PVS1, which it assigns at very strong weight. The exon-14 PTC annotation additionally supports PM5_Strong (PTC), assessed by the codon/residue group.
All five criteria in this group were adjudicated against the governing ENIGMA BRCA1/BRCA2 ACMG/AMP specification v1.2 (ClinGen ENIGMA Expert Panel, doc 1535438831), its Appendices v1.2, and the exon-level Specifications Table 4 declared for PVS1/PM5.
Net contribution from this group: PM5 at Strong strength, via the VCEP's repurposed PM5_VariableWeight (PTC) code. Table 4 pre-assigns 'PM5_Strong (PTC)' to the BRCA2 exon 14 protein-termination row, and this variant is a 7-bp out-of-frame duplication whose new termination codon (p.Tyr2383SerfsTer11, stop ~codon 2393) lies within exon 14 (c.7008-c.7435 / p.2336-p.2479). Exon 14 is not among the BRCA2 PM5_N/A exons (E6, E12, E27).
PS1, PM1, PP2 and BP1 are all not applicable under the governing VCEP rules, not merely unmet: PS1 and BP1 are variant-type restricted (PS1 to identical missense substitutions or matched splice events; BP1_Strong to silent/missense/in-frame alleles) and a frameshift satisfies neither, while PM1 and the classic missense PM5 and PP2 are explicitly withdrawn for BRCA2 ('Do not use'/'N/A') in Table 1 and Appendix J Table 16.
Classic, same-residue PM5 was not applied and no same-residue comparator was found or needed; the strong PM5 call rests entirely on the VCEP's exon-level PTC code, which the specification intends as additional calibrated weight for PTC variants already annotated PVS1.
No residue-level hotspot was found (Cancer Hotspots, 'BRCA2 Y2383'); residue 2383 lies outside both BRCA2 (potentially) clinically important functional domains defined for the bioinformatic codes (PALB2-binding aa 10-40, DNA-binding aa 2481-3186), and SpliceAI max delta is 0.014 (no predicted splice impact).
No source in this group's evidence surface reports this exact variant: it is absent from ClinVar, COSMIC and gnomAD v2.1/v4.1 (also non-cancer subsets), and none of the five fetched full-text papers names c.7141_7147dup or p.Y2383Sfs*11.
PS2 and PM6 are categorically 'Do not use' codes under the governing ENIGMA BRCA2 v1.2 specification (Table 1), so both are not applicable regardless of any de novo finding.
PP1 and BS4 both require a quantitative (Bayesian) co-segregation analysis expressed as a likelihood ratio, per ENIGMA v1.2 Table 1 and Appendix I. The case is a variant-level review with no pedigree, no relative genotypes and no family data for BRCA2 c.7141_7147dup, so neither criterion can be evaluated and both are not assessed rather than met or not met.
No pre-assigned segregation LR for this variant exists in the VCEP tables declared for BS4 (SupplementaryTables_V1.2 ST7 Reference Set; HUMU-40-1557-s001/Parsons 2019), both of which cover missense/splice reference variants only.
This group assessed only PS3 and BS3, the ENIGMA/ClinGen functional-assay codes for BRCA2 (nuclear, autosomal dominant, LOF mechanism established).
The variant NM_000059.4:c.7141_7147dup (p.Tyr2383SerfsTer11) is a frameshift predicted to truncate BRCA2 near the C-terminus, removing the DNA-binding domain (aa 2481-3186) and the C-terminal nuclear localization/RAD51-binding regions.
No variant-specific functional assay exists: the governing curated Table 9 has no entry for this allele, and none of the five fetched functional-theme papers mentions it.
Both PS3 and BS3 are not met. ENIGMA routes mRNA-transcript-only assay data to PVS1_RNA/BP7_RNA, and the exon-level PTC functional inference is captured through the PM5(PTC)/PVS1 exon-weight mechanism, not as a stand-alone PS3 code; no calibrated protein-function assay supports either a damaging (PS3) or a non-damaging (BS3) effect for this specific variant.
All five criteria in this group were adjudicated against the ClinGen ENIGMA BRCA1/BRCA2 Expert Panel Specification v1.2 (cspec), which governs this BRCA2 case; no generic ACMG default overrides it.
The variant NM_000059.4:c.7141_7147dup / NP_000050.3:p.(Tyr2383SerfsTer11) is a 7-bp frameshift duplication absent from ClinVar, COSMIC, cancer hotspots and gnomAD v2.1/v4.1.
PS4 and its negative-direction clinical analogue BP5, together with PP4, all depend on variant-level prevalence/likelihood-ratio data. No such data exist for this allele: the ENIGMA posterior-probability reference set (ST7) and the Parsons et al. 2019 multifactorial table contain no row, and the Li et al. 2020 clinical-history LR table contains only the distinct substitutions c.7141C>G and c.7147T>C. These three criteria are therefore not assessed on the available evidence, with the searched files named explicitly.
PP5 and BP6 require an exact-variant ClinVar expert-panel classification; the variant is absent from ClinVar entirely. Both criteria are additionally declared Not Applicable by the ENIGMA BRCA2 v1.2 specification, so both are recorded as not_applicable.
Direction check applied per criterion: PS4 strengthens high (OR >= 4), PP4 strengthens high (LR >= 2.08), BP5 strengthens low (LR <= 0.48). No numeric value was available for any of the three, so no inequality could be formed; this is recorded as a data gap rather than a met/not_met verdict.
Allelic (phase / co-occurrence / inheritance-mode) evidence is limited to the governing ENIGMA BRCA1/BRCA2 specification v1.2, because the case is a variant-level curation with no proband genotype, phase or Fanconi Anemia phenotype data.
PM3 is gene-specifically repurposed as PM3_VariableWeight and is only available for a co-occurrent BRCA2 P/LP allele in trans (or homozygosity) in a proband with BRCA2-related Fanconi Anemia features; no such co-occurrence and no FA phenotype are documented for c.7141_7147dup, so PM3 is not met.
BP2 is explicitly excluded from use by the specification for BRCA2 (permitted only inside the BS2 framework), so it is not applicable at any strength.
No on-record BRCA2 VCEP file contains a pre-assigned PM3- or BP2-related value for c.7141_7147dup / p.Tyr2383SerfsTer11 / p.Y2383Sfs*11; the variant appears in none of the specification, appendix, supplementary-table or multifactorial-likelihood tables.
All three in-silico criteria assigned to this group are out of scope for NM_000059.4:c.7141_7147dup: the variant is a frameshift duplication with a premature termination codon (NP_000050.3:p.(Tyr2383SerfsTer11)), so it is not missense, in-frame, silent or intronic. PP3 and BP4 under ENIGMA BRCA2 v1.2 cover only missense/in-frame indels inside a (potentially) clinically important functional domain and predicted splice impact (SpliceAI) for silent, missense/in-frame and intronic variants outside donor/acceptor +/-1,2 positions; BP7 covers only synonymous variants (plus the deep-intronic idiom at or beyond +7/-21) where BP4 is met. The available SpliceAI max delta score (0.014) was not applied to any of these criteria because the predictor paths do not extend to truncating variants. No VCEP file pre-assigns a code for PP3, BP4 or BP7 for this variant.
No criteria match.
Met · 2
PVS1Very strongMet at very strong: the BRCA2 exon 14 frameshift PTC p.(Tyr2383SerfsTer11) is pre-assigned PVS1 by ENIGMA Table 4 and lies before the c.9600 NMD boundary.
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Reasoning
NM_000059.4:c.7141_7147dup is a 7-bp duplication in BRCA2 exon 14 that shifts the reading frame and creates a premature termination codon (PTC) 10 codons downstream of Tyr2383 (NP_000050.3:p.(Tyr2383SerfsTer11); stop at codon 2393). VariantValidator reports both breakpoints of the variant within exon 14, and exon 14 spans c.7008-c.7435 (p.2336-p.2479), so the PTC at codon 2393 (approximately c.7177-c.7179) also falls in exon 14. Germline loss of function is an established mechanism of BRCA2-related disease (hereditary breast/ovarian cancer syndrome), and the governing ENIGMA BRCA1/BRCA2 VCEP specification v1.2 retains PVS1 for this gene at variable weight. The variant is a nonsense/frameshift (PTC) variant, so the BRCA2 PVS1 decision tree (Appendix D, Figure 5) and the exon-specific lookup in Specifications Table 4 apply. Table 4's BRCA2 exon 14 PTC row reads 'PVS1 | PTC | PM5_Strong (PTC)', i.e. the ENIGMA VCEP has pre-assigned full-weight PVS1 (very strong) to protein-termination variants in exon 14; a pre-assigned code in this table is the governing answer and outranks any weight computed de novo. No downgrade rule applies: the PTC is far 5' of the c.9600 boundary at which BRCA2 PTCs cease to be predicted to trigger nonsense-mediated decay (Appendix D, Figure 5), so the transcript is NMD-competent, and exon 14 is not among the ENIGMA-designated non-contributing exons (Table 4 marks PVS1_N/A only for the 5'UTR/intron regions of exon 1 and for non-coding/unknown-duplication rows). The allele is predicted to encode a protein truncated by roughly 1025 C-terminal residues (to ~2393 of 3418 aa), removing the entire DNA-binding domain (Table 4 places the BRCA2 DBD from ~p.2481 onward) and both C-terminal nuclear localization signals. Independent functional work supports the loss-of-function expectation for C-terminal BRCA2 truncations: truncated BRCA2 is cytoplasmically excluded and non-functional because NLS1 and NLS3 lie within the final 156 residues (PMID:10570174), and C-terminal BRCA2 truncation markedly impairs homology-directed repair in human CAPAN-1 cells and in Brca2 exon-27-deleted mouse ES cells (PMID:11239455). PVS1 is therefore met, un-downgraded, at strength 'very strong'. The same exon-14 annotation supports PM5_Strong (PTC) for this variant, which is assessed by the codon/residue group, not here.
Rule
ENIGMA BRCA1/BRCA2 VCEP v1.2, Specifications Table 4, BRCA2 exon 14 PTC row ('PVS1 | PTC'), read with Appendix D Figure 5 (BRCA2 PVS1 decision tree; NMD not predicted only for PTC at/after c.9600). Nonsense/frameshift PTC in exon 14 = PVS1 at full weight (very strong).
Evidence considered
ENIGMA/ClinGen BRCA1 and BRCA2 VCEP specification v1.2 (cspec): PVS1 is a 'VERY STRONG' criterion applied at variable weight, with strength and description separated by variant type and applied 'according to PVS1 flowchart, which considers knowledge of clinically important functional domains'; for predicted protein-termination-codon (PTC) variants the code is applied 'with exon-specific weights derived for the PM5 (PTC) code', deferring to Specifications Table 4.
Specifications Table 4 (ENIGMA BRCA2 exon-level PVS1 decision table): BRCA2 E14 row reads 'PVS1 | PTC | PM5_Strong (PTC)' - i.e. for a nonsense/frameshift variant whose PTC lies in exon 14 the pre-assigned PVS1 weight is full (very strong), and PM5_Strong (PTC) also applies. Table 4 notes that PVS1 weights were determined by the comprehensive decision trees in Appendices Section D, and that PM5 (PTC) weight is set by the exon where the termination codon occurs (may differ from the variant position).
Specifications Table 4 exon map for BRCA2: exon 14 covers c.7008-c.7435 (p.2336-p.2479); the variant c.7141_7147dup and its PTC at codon 2393 (~c.7177) both lie inside exon 14.
Appendices v1.2, Appendix D (PVS1 and justification for variable weighting), Figure 5 (BRCA2 PVS1 decision tree - initiation, nonsense/frameshift, deletion, duplication): 'PTC from position c.9600 onwards are not predicted to result in NMD.' The PTC here (~c.7177) is far 5' of c.9600, so the transcript is predicted to be NMD-sensitive and no NMD-escape downgrade applies.
VariantValidator-derived variant record (case data): transcript NM_000059.4, protein NP_000050.3:p.(Y2383Sfs*11)/p.(Tyr2383SerfsTer11), consequence_class frameshift, variant_exonic_positions start_exon 14 / end_exon 14 on both NC_000013.10 and NC_000013.11.
Reviewed PMID:10570174 (Truncated BRCA2 is cytoplasmic) - full text does not name this variant, but demonstrates that BRCA2 truncations removing the C-terminal NLS1/NLS3 region yield cytoplasmically excluded, non-functional protein; used as mechanism-level support only.
Reviewed PMID:11239455 (BRCA2 is required for homology-directed repair of chromosomal breaks) - full text does not name this variant, but shows that a highly truncated BRCA2 (6174delT) and a C-terminal exon-27 deletion both impair HDR; used as mechanism-level support only.
Reviewed PMID:22193408, PMID:24312913 and PMID:20878484 - none names c.7141_7147dup or its protein change; PMID:24312913 and PMID:20878484 describe other truncating BRCA2 frameshifts (providing gene-level frameshift-to-nonfunctional-protein context only), and PMID:22193408 notes that the extreme C-terminal RAD51-binding region may be dispensable for HR in vivo, a general caveat not specific to this allele. None was used to alter the VCEP-assigned PVS1 weight.
Still missing
Searched Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, Specifications_Table4_V1.2_2024-11-18.xlsx.txt and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.7141_7147dup, p.Tyr2383SerfsTer11 and p.Y2383Sfs*11: the exact variant is not named in any of these VCEP files, so PVS1 was assigned from the governing exon-14 rule in Table 4, not from a variant-specific table row.
No mRNA/cDNA transcript analysis specific to this allele was located; NMD-competence is inferred from the ENIGMA PTC/NMD position rule (PTC 5' of c.9600) rather than measured directly.
PM5StrongMet at Strong: ENIGMA Table 4 pre-assigns PM5_Strong (PTC) to BRCA2 exon 14 protein-termination variants, and this frameshift's stop codon falls in exon 14.
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Reasoning
ENIGMA BRCA2 v1.2 repurposes PM5. Table 1 defines 'PM5_VariableWeight (PTC)': 'Repurposing of PM5 code. Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before', applied 'to justify additional weight for PTC variants annotated as PVS1', 'only applied to genomic PTC changes (not splicing)', with the weight 'determined by exon where the nucleotide change occurs', and directs the user to Specifications Table 4 for the per-exon PM5 (PTC) codes. The classic missense reading of PM5 ('missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before') is explicitly not used for BRCA2 (Table 1: 'Do not use. Considered as component of bioinformatic analysis (PP3/BP4)'; Appendix J Table 16: 'N/A. Some residues can harbor pathogenic and non-pathogenic substitutions.'). NM_000059.4:c.7141_7147dup is a 7-nucleotide out-of-frame duplication: the duplicated segment begins at c.7141, the first base of codon 2381, so the reading frame is disrupted from codon 2383 and the HGVS consequence p.(Tyr2383SerfsTer11) places the new termination codon at approximately codon 2393 (11 codons into the new frame). BRCA2 exon 14 spans c.7008-c.7435 (p.2336-p.2479) per Specifications Table 4, so both the variant and the resulting PTC fall inside exon 14; E14 is not in the PM5_N/A set for BRCA2 (which is E6, E12, E27) and is listed among the PM5_PTC-applicable exons. The pre-assigned code for the BRCA2 E14 PTC row in Table 4 is 'PTC / PM5_Strong (PTC)'. Because a pre-assigned code in a declared VCEP table is the governing answer, PM5 is applied here at Strong strength. This is a genomic (not splice-site) PTC change and the allele is the frameshift type that Table 4 covers, so the rule's preconditions hold. Note that both exon 14 and exon 15 carry PM5_Strong (PTC), so the call is insensitive to the exact PTC codon.
ENIGMA BRCA2 v1.2 Table 1, PM5_VariableWeight (PTC): 'Repurposing of PM5 code. Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before... Use to justify additional weight for PTC variants annotated as PVS1. Only applied to genomic PTC changes (not splicing). Weight determined by exon where the nucleotide change occurs. See Table 4, provided as a separate searchable excel file, for PM5 (PTC) codes applicable for predicted termination codon variants - organized by exon.'
ENIGMA BRCA2 v1.2 Table 1, classic PM5 row: 'Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before' - 'Do not use. Considered as component of bioinformatic analysis (PP3/BP4).'; corroborated by Appendix J Table 16 (PM5 = 'N/A. Some residues can harbor pathogenic and non-pathogenic substitutions.').
Specifications Table 4 (BRCA2 sheet): exon 14 spans c.7008-c.7435 (p.2336_2479) and its PTC row reads 'PVS1 | PTC | PM5_Strong (PTC)'. The BRCA2 PM5_N/A exons are E6, E12 and E27; E14 is PM5_PTC-applicable.
Specifications Table 4 read-me: 'PM5 code weights for protein termination variants, determined for each exon, as detailed in Appendices, Section D, Figures 7 and 8. Apply only to genomic PTC changes (not splicing). Weight determined by exon where the termination codon occurs (may not be the same exon as the variant position). Variants at the donor/acceptor +/-1,2 positions do not qualify for PM5 (PTC) code.'
Appendices v1.2, justification for PM5 (PTC) exon-specific weights: 'The per-exon evidence was then summed using a points-based approach (Supporting = 1, Moderate = 2, Strong = 4)... the PM5 (PTC) code can be applied as Strong evidence in favour of pathogenicity for most exons'; 'PM5 (PTC) code can only be applied to germline variants that meet PVS1 codes, namely nonsense and frame-shift changes, including large deletions and tandem duplications.'
Variant consequence: NM_000059.4:c.7141_7147dup -> NP_000050.3:p.(Tyr2383SerfsTer11) (p.(Y2383Sfs*11)), a 7-bp frameshift duplication; the new termination codon is ~11 codons downstream of codon 2383, i.e. within exon 14.
Searched the declared VCEP full texts with grep for 'c.7141_7147dup', 'p.Tyr2383SerfsTer11', 'p.Y2383Sfs*11', 'Y2383' and the exon 14 coordinates; no variant-specific PM5(PTC) row exists, so the exon-level Table 4 row governs.
Still missing
Specifications_Table4_V1.2_2024-11-18.xlsx is exon-level: it contains no variant-level row for c.7141_7147dup or p.Tyr2383SerfsTer11. The Strong weight is inherited from the BRCA2 exon 14 PTC row ('PM5_Strong (PTC)'), and the PTC exon assignment was derived from the HGVS frameshift nomenclature (p.Tyr2383SerfsTer11, stop ~codon 2393) rather than from a variant-specific annotation; the assignment is robust because exon 15 carries the same PM5_Strong (PTC) weight.
No variant-specific PM5 entry was found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, Specifications_Table9_V1.2_2024-11-18.xlsx, SupplementaryTables_V1.2_2024-11-18.xlsx or HUMU-40-1557-s001.xlsx (all searched under c.7141_7147dup / p.Tyr2383SerfsTer11 / p.Y2383Sfs*11).
The collected PM5 comparator artifact located no same-residue missense comparator; that is expected and irrelevant here, because the governing BRCA2 PM5 applies via the repurposed PTC route, not the classic same-residue missense route.
PS3Not met: no variant-specific functional assay exists for c.7141_7147dup, and the governing ENIGMA Table 9 lists no PS3 entry for this allele.
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Reasoning
PS3 requires well-established in vitro or in vivo functional studies supportive of a damaging effect on protein function, with effect measured via protein only or via mRNA and protein combined (ENIGMA BRCA2 specification v1.2, Table 1; Appendix E). For NM_000059.4:c.7141_7147dup (p.Tyr2383SerfsTer11), no variant-specific functional assay evidence exists. The governing curated assay table (Specifications Table 9, the pre-assigned PS3/BS3 source for BRCA2) contains no entry for c.7141_7147dup, p.Tyr2383SerfsTer11 or p.Y2383Sfs*11; searches for the nucleotide change (7141, 7141_7147), the protein change (2383, Y2383, Sfs*11) and the frameshift/duplication notations returned no BRCA2 row for this allele. The five functional-theme publications retrieved for this case (PMID:10570174, PMID:11239455, PMID:20878484, PMID:22193408, PMID:24312913) each analyse gene-level or mechanism-level truncating BRCA2 biology but none names, tables or tests c.7141_7147dup; all were recorded as variant_mentioned = false. The evidence they provide (C-terminal truncation removes the nuclear localization signals and the RAD51-interacting region, and truncated BRCA2 is cytoplasmic/non-functional) is generic to BRCA2 truncating alleles and cannot be transferred to this specific variant as a calibrated PS3 code. Under the ENIGMA specification, mRNA-transcript-only assay results are not applied as PS3 (they are used under PVS1_RNA), and the exon-level functional inference for protein-truncating variants is captured through the PM5(PTC)/PVS1 exon-weight mechanism (Table 4, Appendix D) rather than as a stand-alone PS3 code here. PS3 is therefore not met: no calibrated variant-specific functional evidence supports a damaging effect for this allele.
Rule
ENIGMA BRCA2 v1.2 PS3: Well-established in vitro or in vivo functional studies supportive of a damaging effect; assay measures effect via protein only OR mRNA and protein combined. See Table 9 for code recommendations from calibrated published assays (Figure 1C, Appendix E).
Evidence considered
ENIGMA BRCA2 specification v1.2 Table 1 defines PS3 as well-established in vitro or in vivo functional studies supportive of a damaging effect, applied for assays measuring effect via protein only or via mRNA and protein combined; assays measuring effect via mRNA only are applied under an alternative code (PVS1_RNA).
ENIGMA BRCA2 specification Appendix E states that PS3/BS3 are reserved for variant impact on protein function and that evidence from splicing (mRNA) assays is not assigned PS3/BS3 but noted under PVS1 or BP7; PS3/BS3 assignment must consider assay design, variant location and predicted/observed splicing.
Specifications Table 9 (specs_v1.2 Table9_BRCA12VCEP_specs, 4732 BRCA rows) was searched for every notation of this variant (c.7141_7147dup, p.Tyr2383SerfsTer11, p.Y2383Sfs*11, '7141', '2383'): no row corresponds to this allele. The only c.714x-region BRCA2 row retrieved was the unrelated c.8714A>G p.(Tyr2905Cys).
Appendices v1.2 (PM5(PTC) justification, Appendix D) note that observation of functional impact for a PTC variant in an exon can be used to infer a PS3-type weight for another PTC variant in the same exon, but this inference is built into the exon-specific PM5(PTC) weights (Table 4) and is not a stand-alone variant-specific PS3 code for c.7141_7147dup.
PMID:10570174 (Quade et al.): GFP-tagged BRCA2 constructs lacking the C-terminal region, and the endogenous 6174delT truncation, are cytoplasmically localised; the paper concludes truncation mutants fail to translocate to the nucleus and are non-functional. Gene-level mechanism only; the specific variant c.7141_7147dup is not named or tested (searched_for: c.7141_7147dup, p.(Y2383Sfs*11), Y2383Sfs*11).
PMID:11239455 (Moynahan et al.): BRCA2 is required for homology-directed repair; CAPAN-1 cells (6174delT) show >100-fold reduced HDR and Brca2 exon 27 deletion reduces HDR 5-6-fold. Establishes that C-terminal truncation impairs recombination, but no data on c.7141_7147dup (variant_mentioned: false).
PMID:20878484: reports a different Italian-family BRCA2 frameshift (7525_7526insT, p.Ser2509fs) truncating by 881 amino acids; the queried variant is not reported. Gene-level mechanism context only.
PMID:22193408 and PMID:24312913: narrative reviews confirming BRCA2 tumour suppression operates through RAD51 recruitment/homologous recombination and that C-terminal truncations (DBD, NLS, Rad51-binding motif) are non-functional. Neither mentions c.7141_7147dup.
Still missing
Searched Specifications_Table9_V1.2_2024-11-18.xlsx (ENIGMA BRCA2 curated functional assay table) in full: no entry for c.7141_7147dup, p.Tyr2383SerfsTer11 or p.Y2383Sfs*11, and no BRCA2 row at c.7141; the table curates predominantly missense/synonymous variants. A variant-specific PS3 code is therefore not available from this source.
Searched Appendices_V1.2_2024-11-18.docx (Appendix E, Figure 9; Appendix D PTC inference text) and Specifications_V1.2_2024-11-18.docx (Table 1 PS3 rule, lines 78-93) for any variant-specific or same-exon functional data applicable to c.7141_7147dup: none specific to this allele.
No primary functional study assaying c.7141_7147dup (e.g. HDR/complementation or SGE) was retrieved; the five fetched papers do not mention the variant. PS3 could be revisited if a calibrated protein-function assay for this allele becomes available.
PM3Not met: no Fanconi Anemia phenotype and no co-occurrent pathogenic BRCA2 allele in trans are reported, which the VCEP PM3_VariableWeight rule requires.
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Reasoning
Governing framework: ClinGen ENIGMA BRCA1/BRCA2 specification v1.2, where PM3 is restricted (PM3_VariableWeight) to a proband with a phenotype consistent with BRCA1-/BRCA2-related Fanconi Anemia (FA) who carries the variant under assessment in trans with (or as a homozygote with) a co-occurrent pathogenic/likely pathogenic variant in the same gene; points are awarded per proband (Table 6 / Appendix H: 2 points for P/LP in trans or homozygote, 1 point for phase unknown, summed to PM3_Strong >=4, PM3 =2, PM3_Supporting =1). This case provides no proband-level genotype or phenotype data: nothing in the case evidence describes FA features (no DEB/MMC or spontaneous chromosome breakage result, no FA physical features, no FA-type pathology, no cancer diagnosis <=5 years), and no second BRCA2 variant in trans, homozygosity, or phase information is reported for c.7141_7147dup. The observation is a heterozygous germline frameshift in an autosomal dominant BRCA2-related cancer predisposition context (MONDO:0700269), which is not the biallelic/recessive configuration PM3 requires. Because no co-occurrent pathogenic BRCA2 allele and no FA-consistent phenotype are documented, the PM3 precondition is not satisfied and the criterion is not met rather than assigned at any strength. Absence of a benign population code alone (variant absent from gnomAD v2.1/v4.1) does not substitute for the required trans/homozygote observation.
Rule
ENIGMA BRCA1/BRCA2 specification v1.2, PM3_VariableWeight: apply only for a proband with a phenotype consistent with BRCA1-/BRCA2-related Fanconi Anemia and a co-occurrent P/LP variant in the same gene; 2 points if P/LP in trans or homozygote, 1 point if phase unknown; sum across probands gives PM3_Supporting =1, PM3 =2, PM3_Strong >=4.
Evidence considered
ENIGMA BRCA1/BRCA2 specification v1.2 Table 1 (PM3 row): PM3 is not applied for BRCA2 in the generic recessive sense; it is PM3_VariableWeight, applicable only for a patient with a phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia plus co-occurrent variants in the same gene, with the co-occurrent P/LP variant classified using VCEP specifications and the variant under assessment required to be sufficiently rare (not meeting a benign population evidence code).
ENIGMA specification v1.2 Table 6 / Appendix H Table 12: points per FA-affected proband are 2 for a P or LP variant in trans (or homozygote) and 1 for phase unknown; final code from the summed points is PM3_Strong >=4, PM3 =2, PM3_Supporting =1.
Appendix H: co-occurrence in trans may be met by genotyping of at least one parent, or assumed when the VUA is seen with at least 2 different P/LP variants, or inferred for a homozygote FA-affected patient from a consanguineous union. None of these in-trans stipulations is documented for this variant in the case evidence.
No co-occurrent BRCA2 pathogenic/likely pathogenic variant, no homozygosity and no parental or offspring genotyping is reported anywhere in the case evidence for c.7141_7147dup.
No Fanconi Anemia phenotypic information (DEB/MMC or spontaneous chromosome breakage, FA physical features, FA-type pathology/laboratory findings, or cancer diagnosis <=5 years) is reported in the case evidence; the case carries no proband-level clinical description.
BRCA2 is curated here in its autosomal dominant context (BRCA2-related cancer predisposition); the case bundle contains gene-level background that biallelic BRCA2 loss causes Fanconi anemia complementation group D1, but no such biallelic observation for this variant is documented.
Biallelic/haplotype evidence sources checked: the Li et al. 2020 BRCA2 clinical-history LR table (PMID:31853058) and the Easton et al. 2007 (PMID:17924331) co-occurrence/multifactorial dataset were searched for 'c.7141_7147dup' and the p.Y2383Sfs*11 notations; neither contains an entry for this variant (the only c.7141-adjacent row in the Li table is for the unrelated substitution c.7141C>G).
All five retrieved full texts (PMID:10570174, PMID:11239455, PMID:20878484, PMID:22193408, PMID:24312913) were checked for the variant under both coding and protein notations; none reports c.7141_7147dup / p.Tyr2383SerfsTer11 / p.Y2383Sfs*11, so none provides a phase, trans/cis or co-occurrence observation that could support PM3.
Still missing
No proband-level genotype data (presence/phase of a second BRCA2 variant, homozygosity, or parental genotyping) is present in the case evidence bundle; the case is a variant-level curation of a heterozygous germline finding.
No proband phenotype information (chromosome breakage testing by DEB/MMC or spontaneous breakage, FA physical features, FA-type pathology/laboratory findings, or cancer diagnosis <=5 years) is present, so a BRCA2-related FA phenotype could not be confirmed or excluded.
Searched Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx and all other on-record BRCA2 VCEP files (Specifications_Table4/Table9, SupplementaryTables, HUMU-40-1557-s001, PMID_31853058_BRCA2_clinical_history_LR) for 'c.7141_7147dup', 'p.Tyr2383SerfsTer11' and 'p.Y2383Sfs*11': no entry for this variant appears in any of them, so there is no pre-assigned PM3-related point value on record for it.
BA1Not met: the variant is absent from gnomAD v2.1/v4.1 and non-cancer subsets (FAF 0), far below the VCEP BA1 threshold of 0.001.
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Reasoning
The governing ENIGMA BRCA1/BRCA2 specification v1.2 defines BA1 (Benign Stand-Alone) as a filter allele frequency (FAF) > 0.001 (> 0.1%) in gnomAD v2.1 (non-cancer, exome-only subset) and/or gnomAD v3.1 (non-cancer), in a non-founder population. NM_000059.4:c.7141_7147dup is absent from every gnomAD dataset queried: all-comers v2.1 (GRCh37) and v4.1 (GRCh38), the gnomAD v2.1 non-cancer exome subset, and the gnomAD v3.1 non-cancer genome set. Its FAF is therefore 0, orders of magnitude below the 0.001 stand-alone threshold, so BA1 does not apply. Concordantly, the ClinGen SVI generic default for BA1 (>= 0.05, PMID:25741868) is even further out of reach. Note that the VCEP applies BA1/BS1 as filter (not minor) allele frequency in non-founder populations and excludes well-established pathogenic founder variants and low-depth (< 20) sites; none of those qualifications changes an absence-based result.
ENIGMA v1.2 specifies BA1 as FAF > 0.001 (> 0.1%) in gnomAD v2.1 (non-cancer, exome-only subset) and/or gnomAD v3.1 (non-cancer), non-founder populations, using highest filter allele frequency with exome and genome data assessed separately and read depth >= 20.
Appendix G documents the BA1 derivation via the Whiffin allele-frequency calculator (prevalence 0.125, genetic heterogeneity 0.01, allelic heterogeneity 1.00, BRCA2 penetrance 0.69, PMID:28632866), yielding a minimal credible allele frequency of 0.000906 rounded to 0.001 for BRCA2.
gnomAD v2.1 non-cancer exome-only subset: absent. gnomAD v3.1 non-cancer genomes: absent. Both datasets named by the governing VCEP for BA1/BS1/PM2 return no entry for this variant.
ClinVar returns no entry for this variant ('This variant is absent from ClinVar'), so there is no conflicting or supporting classification to weigh for a frequency-based code.
Generic ACMG/AMP default BA1 of >= 0.05 (PMID:25741868) is not reached either, but the governing ENIGMA specification (0.001) takes precedence and is likewise not reached.
Still missing
No entry for c.7141_7147dup, p.Tyr2383SerfsTer11 or p.Y2383Sfs*11 exists in any declared VCEP file: searched Specifications_V1.2_2024-11-18.docx (full text), Appendices_V1.2_2024-11-18.docx (full text), HUMU-40-1557-s001.xlsx (SuppT1-SuppT5, Parsons et al. 2019), SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_Table4_V1.2_2024-11-18.xlsx and Specifications_Table9_V1.2_2024-11-18.xlsx. The only nearby records are the distinct substitutions c.7141C>G and c.7147T>C; there is no pre-assigned code for this duplication.
gnomAD-Canada v1.0 could not be queried (connection reset by peer); this dataset is not part of the ENIGMA BA1 definition, which names only gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, so the absence-based result is unaffected.
BS1Not met: the variant is absent from gnomAD v2.1/v4.1 and non-cancer subsets (FAF 0), below the VCEP BS1 threshold of 0.0001.
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Reasoning
The governing ENIGMA BRCA1/BRCA2 specification v1.2 defines BS1 (Benign Strong) as a filter allele frequency (FAF) > 0.0001 (> 0.01%) in gnomAD v2.1 (non-cancer, exome-only subset) and/or gnomAD v3.1 (non-cancer), non-founder populations, with a Supporting tier for FAF > 0.00002 and <= 0.0001. NM_000059.4:c.7141_7147dup is absent from gnomAD v2.1 (all-comers), gnomAD v4.1 (all-comers), the gnomAD v2.1 non-cancer exome subset, and gnomAD v3.1 non-cancer. Its FAF is 0, which fails both the Strong and Supporting BS1 thresholds; a variant observed only once, or at MAF > 0 to <= 0.00002, is explicitly uninformative under Appendix G. The generic SVI default of >= 0.01 (PMID:28518168) is also not approached. BS1 is therefore not met at any strength.
ENIGMA v1.2 BS1_Strong requires FAF > 0.0001; BS1_Supporting requires FAF > 0.00002 and <= 0.0001, in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes for non-founder populations.
Appendix G derives BS1 via the Whiffin calculator (prevalence 0.125, genetic heterogeneity 0.01, allelic heterogeneity 0.10, BRCA2 penetrance 0.69, PMID:28632866), giving a minimal credible allele frequency of 0.0000906 rounded to 0.0001 for BRCA2, with the LR-based approach giving LR 0.03 (Benign Strong) for MAF > 0.0001 to <= 0.001.
gnomAD v2.1 and v4.1 all-comers totals both report the variant as absent (found=false).
gnomAD v2.1 non-cancer exome-only subset and gnomAD v3.1 non-cancer genomes both report the variant as absent.
Appendix G states that observation of a variant only once in a gnomAD outbred population, and maximum MAF > 0 to <= 0.00002, are not informative, so no weaker frequency code can be salvaged from a non-observation.
Still missing
No entry for c.7141_7147dup, p.Tyr2383SerfsTer11 or p.Y2383Sfs*11 was found in any declared VCEP file searched in full text: Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, HUMU-40-1557-s001.xlsx (Parsons et al. 2019 SuppT1-SuppT5), SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_Table4_V1.2_2024-11-18.xlsx and Specifications_Table9_V1.2_2024-11-18.xlsx; no pre-assigned frequency code exists for this variant.
gnomAD-Canada v1.0 was unreachable (connection reset by peer). It is not one of the datasets named in the ENIGMA BS1 definition, so this does not affect the result.
BS2Not met: no genotype-positive probands were reported, so zero Table 8 points accrued toward the >= 1 point required for BS2_Supporting.
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Reasoning
In the ENIGMA BRCA1/BRCA2 specification v1.2, BS2 is repurposed from the generic ACMG 'observed in a healthy adult' code into a variable-weight, proband-scoring criterion applied in the absence of a Fanconi Anemia (FA) phenotype. It is awarded only for individuals who carry the variant under assessment together with a co-occurring pathogenic/likely pathogenic BRCA2 allele (or as a homozygote), scored via Table 8: BS2_Supporting requires >= 1 point, BS2_Moderate >= 2 points, BS2 >= 4 points. No proband carrying NM_000059.4:c.7141_7147dup was identified in this case, and no phase, co-occurrence, cancer-onset-age or cancer-unaffected-age data exist for such individuals; consequently zero Table 8 points can be accrued and even the BS2_Supporting threshold is unreachable. The variant is absent from gnomAD, so the Table 8 footnote route (>= 2 homozygotes in gnomAD, already captured by BA1/BS1) also yields nothing. BS2 is therefore not met.
Rule
ENIGMA BRCA2 v1.2 BS2_VariableWeight (Specifications Table 8): points per proband with a co-occurring pathogenic allele and absence of Fanconi Anemia features — BS2 >= 4 points; BS2_Moderate = 2; BS2_Supporting = 1.
Evidence considered
ENIGMA v1.2 BS2_VariableWeight: 'Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype', with final weight from the sum of BS2-related points (BS2 >= 4 points; BS2_Moderate = 2 points; BS2_Supporting = 1 point) per Specifications Table 8.
Table 8 assigns points per proband for a variant in trans with a pathogenic/likely pathogenic allele in the same gene (4 points if first cancer onset > 50y or cancer-unaffected > 50y), as a homozygote (2 points), or with phase unknown (1 point), with lower points for earlier onset — none of these presentations was observed for this variant.
Table 8 footnote: homozygote points apply only to phenotyped individuals from clinical or research cohorts, not to frequency-based observations; variants seen as >= 2 gnomAD homozygotes are already captured by BA1/BS1. This variant is absent from gnomAD, so no such observation exists.
Appendix H sets out the FA phenotype definitions and the biallelic BRCA2 (FA-D1) context underlying PM3/BS2; no FA-affected proband with this variant was reported in the case evidence.
ClinVar has no submission for this variant, so no co-occurrence or phase information could be drawn from a curated record.
Still missing
No proband-level data (co-occurring BRCA2 pathogenic variant, phase, cancer-onset age, or cancer-unaffected age at last follow-up) were available for any individual carrying c.7141_7147dup, so the Table 8 point system could not be exercised; the criterion is assessed as not met rather than as a data-collection gap because no carrier was reported at all.
No entry for c.7141_7147dup, p.Tyr2383SerfsTer11 or p.Y2383Sfs*11 was found in any declared VCEP file searched in full text (Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, HUMU-40-1557-s001.xlsx, SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_Table4 and Table9); the BS2/PM3 point tables (Specifications Table 8 / Appendix H) are methodology references rather than variant lookups and contain no variant-specific pre-assigned code.
BS3Not met: no functional assay of c.7141_7147dup was found reporting retained function, and the governing ENIGMA Table 9 lists no BS3 entry for this allele.
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Reasoning
BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function, with effect measured via protein only or via mRNA and protein combined (ENIGMA BRCA2 specification v1.2, Table 1; Appendix E). No functional study of c.7141_7147dup (p.Tyr2383SerfsTer11) exists, and no source reports a benign (normal-function) result for this allele. Specifications Table 9 contains no entry for c.7141_7147dup, p.Tyr2383SerfsTer11 or p.Y2383Sfs*11, so no pre-assigned BS3 code applies. The five functional-theme publications retrieved do not mention the variant and none provides a normal-function assay result for it. Additionally, general assay evidence and mechanistic data are strongly in the opposite direction: this frameshift truncates the BRCA2 protein within the C-terminal region (DNA-binding domain aa 2481-3186 and the C-terminal nuclear localization signals/RAD51-interacting motif), and the literature consistently shows such C-terminal truncations are non-functional (PMID:10570174, PMID:11239455). BS3 is therefore not met: there is no functional evidence of a non-damaging effect, and the biological expectation is the reverse.
Rule
ENIGMA BRCA2 v1.2 BS3: Well-established in vitro or in vivo functional studies shows no damaging effect on protein function; assay measures effect via protein only OR mRNA and protein combined. See Table 9 for code recommendations from calibrated published assays (Figure 1C, Appendix E). Not applied when conflicting results are present from well-established assays with sufficient controls.
Evidence considered
ENIGMA BRCA2 specification v1.2 Table 1 defines BS3 as well-established in vitro or in vivo functional studies showing no damaging effect on protein function, applied for assays measuring effect via protein only or via mRNA and protein combined; mRNA-only assays are applied under an alternative code (BP7_RNA).
Specification Table 1 instructs that BS3 must be documented using Specifications Table 9 for calibrated published assays, and that BS3 should not be applied when conflicting results are present from well-established assays with sufficient controls (Figure 1C).
Specifications Table 9 was searched for every notation of this variant (c.7141_7147dup, p.Tyr2383SerfsTer11, p.Y2383Sfs*11, '7141', '2383'): no BRCA2 row for this allele, hence no curated BS3 recommendation.
PMID:10570174 reports that BRCA2 truncation mutants lacking the C-terminal region (including the nuclear localization signals) are cytoplasmically localised and non-functional, arguing against a non-damaging effect for a frameshift truncating at codon 2383.
PMID:11239455 reports >100-fold reduction in homologous recombination in CAPAN-1 cells carrying a C-terminal BRCA2 truncation and a 5-6-fold HDR reduction with exon 27 deletion, again arguing against retained function for C-terminal truncating alleles.
Still missing
Searched Specifications_Table9_V1.2_2024-11-18.xlsx (ENIGMA BRCA2 curated functional assay table) in full for c.7141_7147dup, p.Tyr2383SerfsTer11 and p.Y2383Sfs*11: no entry, so no pre-assigned BS3 code exists for this variant.
No primary functional study testing c.7141_7147dup for retained/normal function was retrieved; the five fetched functional-theme papers do not mention this allele, so a variant-specific BS3 cannot be established.
PS4Not assessed: no case-control dataset exists for this frameshift, and no declared PS4 table contains an entry for c.7141_7147dup (OR >= 4 required).
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Reasoning
Governing framework: ClinGen ENIGMA BRCA1/BRCA2 Expert Panel Specification v1.2 (cspec), PS4 = 'The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0).' The operator is high-supports-pathogenic: met requires OR >= 4 with p <= 0.05. There is no case-control study (and no case-control LR) for NM_000059.4:c.7141_7147dup / NP_000050.3:p.(Tyr2383SerfsTer11). The variant is absent from ClinVar, COSMIC and cancer hotspots and absent from gnomAD v2.1 and v4.1, so no affected-vs-control comparison can be formed and the inequality cannot be evaluated. ENIGMA further states proband counting must not be used as originally described, so PS4_Moderate cannot be assigned from case observations. The declared PS4 sources were searched under all three notations (c.7141_7147dup, p.Tyr2383SerfsTer11, p.Y2383Sfs*11): the converted full text of SupplementaryTables_V1.2_2024-11-18.xlsx (ST7 Reference Set Vts sheet, ~380 BRCA2 rows) contains no row for this variant, and HUMU-40-1557-s001.xlsx (Parsons et al. 2019 multifactorial data) contains no row for this variant. Conclusion: no case-control enrichment evidence exists; PS4 is not available and is therefore not assessed.
Rule
PS4 (ENIGMA BRCA2 v1.2, Strong): 'The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0).' High-supports-pathogenic: met requires OR >= 4.
Evidence considered
ENIGMA BRCA1/BRCA2 v1.2 specification (cspec) PS4 rule: 'Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0).' PS4_Moderate via proband counting is explicitly disallowed ('Do not use Proband Counting as originally described.').
ClinVar searched with BRCA2[GENE] AND c.7141_7147dup[VARNAME], NM_000059.4:c.7141_7147dup, and NC_000013.10:g.32929131_32929137dup - exact_match=false, no submissions; 'This variant is absent from ClinVar.'
gnomAD v2.1 and v4.1: variant absent (no allele counts), so no population denominator exists for a case-control comparison.
SupplementaryTables_V1.2_2024-11-18.xlsx converted full text searched (ST7 Reference Set Vts sheet) for c.7141_7147dup / p.(Tyr2383SerfsTer11) / p.Y2383Sfs*11 - no matching row.
HUMU-40-1557-s001.xlsx (Parsons et al. 2019) converted full text searched for 7141/7147 and the protein change - no matching row.
COSMIC and cancerhotspots: no record / not a significant hotspot, giving no somatic case enrichment signal.
Still missing
No case-control OR or case-control LR is available for c.7141_7147dup anywhere in the evidence set; the variant is absent from ClinVar, COSMIC and gnomAD v2.1/v4.1, so PS4 cannot be evaluated.
SupplementaryTables_V1.2.xlsx (declared for PS4/BS4) ST7 Reference Set Vts sheet: searched in full under c.7141_7147dup, p.Tyr2383SerfsTer11 and p.Y2383Sfs*11 - no entry for this variant. Note: case coverage artifact vcep_file_coverage.json flags this file as 'could not be converted to text', but a converted full text (SupplementaryTables_V1.2_2024-11-18.xlsx.txt) was present and was searched directly.
HUMU-40-1557-s001.xlsx (Parsons et al. 2019, PMID:31131967) SuppT1/SuppT4: no row for this variant under any notation searched (missense/synonymous/splice-site reference set only; a frameshift is structurally outside this table's scope).
PP1Not assessed: no pedigree or relative genotypes exist for this variant, so the ENIGMA-required quantitative co-segregation LR (PP1 threshold >= 2.08:1) cannot be computed.
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Reasoning
ENIGMA BRCA2 v1.2 applies PP1 only on the basis of co-segregation of the variant with disease in multiple affected family members, measured by a quantitative (Bayesian) co-segregation method and converted to a code strength through likelihood-ratio thresholds: PP1 supporting LR >= 2.08:1; PP1_Moderate LR >= 4.3:1; PP1_Strong LR >= 18.7:1; PP1_Very Strong LR >= 350:1. Appendix I specifies that the preferred method is a Bayesian analysis of age-specific penetrance in the family (Thompson et al. 2003, PMID:12900794), implemented via COOL or CAL-Leiden, and that Bayes scores from multiple families with the same variant may be combined multiplicatively; a single-family score additionally requires excluding another causative pathogenic variant in the same gene before a Very Strong weight can be used. The case evidence contains no pedigree, no genotype data for affected or unaffected relatives, and no co-segregation LR for c.7141_7147dup; there is no proband-level family history at all. A quantitative co-segregation analysis cannot be run on the available data, so PP1 cannot be assessed. The VCEP tables were also searched for a pre-assigned segregation LR for this variant: the converted SupplementaryTables_V1.2_2024-11-18.xlsx (sheet ST7 Reference Set Vts, containing the per-variant prior/posterior probabilities and IARC classes) and HUMU-40-1557-s001.xlsx (Parsons et al. 2019, PMID:31131967) contain no entry for c.7141_7147dup or p.(Y2383Sfs*11); both tables are reference sets of missense/synonymous (and splice) variants, and this frameshift variant is not represented. No pre-assigned PP1 weight therefore exists to substitute for the missing analysis.
Rule
ENIGMA BRCA2 v1.2 (Table 1, PP1_VariableWeight; Appendix I): co-segregation with disease in multiple affected family members measured by quantitative (Bayesian) co-segregation analysis. Assign weight by Bayes/LR score: PP1 supporting LR >= 2.08:1; PP1_Moderate LR >= 4.3:1; PP1_Strong LR >= 18.7:1; PP1_Very Strong LR >= 350:1. Very Strong requires a predicted/proven effect on protein or mRNA splicing and exclusion of another causative pathogenic variant when a single family is used.
Evidence considered
ENIGMA BRCA2 v1.2 Table 1 (Specifications_V1.2_2024-11-18.docx, PP1 row) defines PP1_VariableWeight as co-segregation with disease in multiple affected family members, with weights assigned by Bayes score: PP1 LR >= 2.08:1; PP1_Moderate LR >= 4.3:1; PP1_Strong LR >= 18.7:1; PP1_Very Strong LR >= 350:1, and refers to Appendix I.
Appendix I of Appendices_V1.2_2024-11-18.docx states the preferred method is Bayesian co-segregation analysis of age-specific penetrance given population disease prevalence (Thompson et al. 2003, PMID:12900794), recommends the online tools COOL and CAL-Leiden, allows multiplicative combination of Bayes scores across families, and requires exclusion of another causative pathogenic variant in the same gene when the score derives from a single family (or an isolated population) before assigning a Very Strong weight.
Appendix I gives the LR-to-strength thresholds for PP1/BS4 as derived from Tavtigian et al. 2018 (PMID:29300386): pathogenic very strong >= 350:1, strong >= 18.7:1, moderate >= 4.30:1, supporting >= 2.08:1; benign very strong <= 0.00285:1, strong <= 0.05:1, moderate <= 0.23:1, supporting <= 0.48:1.
The case evidence bundle (review_manifest.json, case_summary.json, source_registry.json, evidence.json, literature_pass.json, fulltext_map.json, paper_extracts.json) contains no pedigree, no proband family history, no relative genotypes and no co-segregation LR for BRCA2 c.7141_7147dup; the variant-level case records only variant, frequency, in-silico, splicing and Oncokb/COSMIC/hotspot data.
Direct grep of the BRCA2 VCEP fulltext directory for 'c.7141_7147dup', '7141_7147', 'p.(Y2383Sfs*11)', 'Y2383Sfs*11', 'SfsTer' and '2383Sfs' returned no hit for this variant; the only '7141' occurrence in the VCEP tables is an unrelated BRCA2 missense entry, c.7141C>G, in the Li et al. 2020 clinical-history LR file.
The five full-text papers in this case (PMID:10570174, PMID:11239455, PMID:20878484, PMID:22193408, PMID:24312913) report no family or segregation data for c.7141_7147dup; per their pre-computed extracts the variant is not mentioned in any of them.
Still missing
No family pedigree, no genotype data for affected or unaffected relatives, and no co-segregation likelihood ratio for BRCA2 c.7141_7147dup are present anywhere in the case evidence; PP1 cannot be evaluated without a quantitative co-segregation analysis (COOL or CAL-Leiden per ENIGMA Appendix I).
Searched SupplementaryTables_V1.2_2024-11-18.xlsx (sheet ST7 Reference Set Vts) for c.7141_7147dup, p.(Y2383Sfs*11) and p.Y2383Sfs*11: no entry found. The index for this file states the converted full text was unavailable, but a converted text ('SupplementaryTables_V1.2_2024-11-18.xlsx.txt') was located in the BRCA2 fulltext directory and searched directly; ST7 holds missense/synonymous reference-set variants and does not list this frameshift.
Searched HUMU-40-1557-s001.xlsx (Parsons et al. 2019, PMID:31131967) for c.7141_7147dup and p.(Y2383Sfs*11): no entry found; the table covers missense and splicing variants only.
PP4Not assessed: no combined clinical likelihood ratio exists for this variant, and ENIGMA PP4 requires LR >= 2.08.
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Reasoning
Governing framework: ClinGen ENIGMA BRCA1/BRCA2 Specification v1.2 (cspec), PP4_Variable Weight: 'Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data. PP4 - LR >=2.08:1; PP4_Moderate - LR>=4.3:1; PP4_Strong - LR>=18.7:1; PP4_Very Strong - LR>=350:1. Combined LR 1.00 to <2.08 is not informative (PP4 not applicable).' The operator is high-supports-pathogenic: met requires combined clinical LR >= 2.08. The designated variant-level source, PMID_31853058_BRCA2_clinical_history_LR.xlsx (Li et al. 2020, MOESM3 with an added LR = exp(LOG(LR)) column), was searched for BRCA2 HGVS_Nucleotide c.7141_7147dup and the protein notations p.Tyr2383SerfsTer11 / p.Y2383Sfs*11: no row exists for this variant. The nearest rows are the distinct single-base substitutions c.7141C>G (LR 0.5045) and c.7147T>C (LR 0.8598), which are not this 7-bp duplication. HUMU-40-1557-s001.xlsx (Parsons et al. 2019) and Easton et al. 2007 (PMID:17924331) likewise provide no variant-specific clinical LR for this allele. With no combined clinical LR, no value can be compared against the >= 2.08 threshold and PP4 cannot be applied.
Rule
PP4 (ENIGMA BRCA2 v1.2, Variable Weight): combined clinical LR >=2.08 (Supporting), >=4.3 (Moderate), >=18.7 (Strong), >=350 (Very Strong); LR 1.00 to <2.08 not informative. High-supports-pathogenic: met requires combined LR >= 2.08.
Evidence considered
ENIGMA BRCA2 v1.2 PP4 thresholds (cspec): PP4 LR >=2.08:1, Moderate >=4.3:1, Strong >=18.7:1, Very Strong >=350:1; combined LR 1.00 to <2.08 is not informative (PP4 not applicable).
PMID_31853058_BRCA2_clinical_history_LR.xlsx searched for Gene=BRCA2 with HGVS_Nucleotide c.7141_7147dup and protein p.Tyr2383SerfsTer11/p.Y2383Sfs*11 - no matching row. Nearest rows: c.7141C>G (LOG(LR) -0.6841, LR 0.5045) and c.7147T>C (LOG(LR) -0.1511, LR 0.8598).
HUMU-40-1557-s001.xlsx (Parsons et al. 2019) searched for 7141/7147 and the protein change - no matching variant row.
Easton et al. 2007 (PMID:17924331) searched for 7141/7147/2383 - no variant-specific entry; paper establishes the co-occurrence + family-history + cosegregation multifactorial LR methodology only.
Still missing
PMID_31853058_BRCA2_clinical_history_LR.xlsx (the designated PP4/BP5 variant-level source) contains no row for c.7141_7147dup / p.Tyr2383SerfsTer11 / p.Y2383Sfs*11; searched in full. Only the distinct substitutions c.7141C>G (LR 0.5045) and c.7147T>C (LR 0.8598) are present.
No multifactorial likelihood clinical data (co-occurrence, family history, tumour pathology, segregation) could be assembled for this exact variant, so no combined clinical LR exists for PP4.
HUMU-40-1557-s001.xlsx (Parsons et al. 2019) and Easton et al. 2007 (PMID:17924331) contain no variant-specific entry for this allele; they are missense/splice-oriented reference sets.
BS4Not assessed: no family segregation data exist for this variant, so the ENIGMA-required co-segregation LR (BS4 supporting <= 0.48:1) cannot be computed.
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Reasoning
Under ENIGMA BRCA2 v1.2, BS4 is a variable-weight benign code applied for lack of segregation in affected members of a family, measured by the same quantitative co-segregation method used for PP1 and converted via likelihood-ratio thresholds: BS4_Supporting LR <= 0.48 to > 0.23:1; BS4_Moderate LR <= 0.23:1; BS4 (strong) LR <= 0.05:1; BS4_Very Strong LR <= 0.00285:1. Appendix I directs use of COOL or CAL-Leiden and stipulates that a Benign Very Strong weight is only justified after considering bi-linearity as an explanation for the negative co-segregation. The case evidence contains no pedigree, no segregation of the variant among affected and unaffected relatives, and no co-segregation likelihood ratio for c.7141_7147dup; there is no family data of any kind. Without a quantitative co-segregation score, no BS4 threshold can be evaluated, so BS4 is not assessed. The VCEP tables declared for BS4 were searched directly for a pre-assigned value: neither SupplementaryTables_V1.2_2024-11-18.xlsx (ST7 Reference Set Vts) nor HUMU-40-1557-s001.xlsx (Parsons et al. 2019, PMID:31131967) contains an entry for c.7141_7147dup or p.(Y2383Sfs*11), so no pre-assigned BS4 weight exists for this variant either.
Rule
ENIGMA BRCA2 v1.2 (Table 1, BS4_VariableWeight; Appendix I): lack of segregation in affected members of a family measured by quantitative co-segregation analysis. Assign weight by Bayes/LR score: BS4_Supporting LR <= 0.48:1; BS4_Moderate LR <= 0.23:1; BS4 (strong) LR <= 0.05:1; BS4_Very Strong LR <= 0.00285:1. Very Strong requires assessment of bi-linearity.
Evidence considered
ENIGMA BRCA2 v1.2 Table 1 (Specifications_V1.2_2024-11-18.docx, BS4_VariableWeight row) defines BS4 as lack of segregation in affected members of a family with weight assigned by Bayes score: BS4_Supporting LR <= 0.48 to > 0.23:1; BS4_Moderate LR <= 0.23:1; BS4 (strong) LR <= 0.05:1; BS4_Very Strong LR <= 0.00285:1, referring to Appendix I.
Appendix I of Appendices_V1.2_2024-11-18.docx applies the same quantitative Bayesian co-segregation method to PP1 and BS4 (COOL or CAL-Leiden), cites the LR thresholds from Tavtigian et al. 2018 (PMID:29300386), and stipulates that a Benign Very Strong code requires assessment of bi-linearity as an explanation for negative co-segregation.
The case evidence bundle contains no pedigree and no segregation data for BRCA2 c.7141_7147dup; no relative genotypes, no non-segregation observation and no co-segregation LR are recorded.
Genotype-specific segregation data for this variant are also insufficient at the population level for BS4 purposes: gnomAD v2.1 and v4.1 report the variant absent (relevant only to PM2/BS1/BA1, not to BS4), and no family-based data exist.
Direct grep of the BRCA2 VCEP fulltext directory for 'c.7141_7147dup', '7141_7147', 'p.(Y2383Sfs*11)' and 'Y2383Sfs*11' returned no entry for this variant in any declared VCEP file, including the two tables declared for BS4 (SupplementaryTables_V1.2_2024-11-18.xlsx and HUMU-40-1557-s001.xlsx).
Still missing
No multigeneration pedigree with variant genotypes in affected and unaffected relatives is available for BRCA2 c.7141_7147dup, so no co-segregation likelihood ratio can be estimated and no BS4 weight (supporting LR <= 0.48:1 through very strong LR <= 0.00285:1) can be assigned; a quantitative analysis with COOL or CAL-Leiden (ENIGMA Appendix I) is required.
Searched SupplementaryTables_V1.2_2024-11-18.xlsx (sheet ST7 Reference Set Vts) for c.7141_7147dup, p.(Y2383Sfs*11) and p.Y2383Sfs*11: no entry found. The gene index lists this file as unable to be converted, but a converted text ('SupplementaryTables_V1.2_2024-11-18.xlsx.txt') was present in the BRCA2 fulltext directory and was searched directly; ST7 contains missense/synonymous reference-set variants only.
Searched HUMU-40-1557-s001.xlsx (Parsons et al. 2019, PMID:31131967) for c.7141_7147dup and p.(Y2383Sfs*11): no entry found; SuppT1 covers BRCA1/2 missense and splicing variants only, and this frameshift variant is not represented.
BP5Not assessed: no multifactorial clinical likelihood ratio exists for this variant, and ENIGMA BP5 requires LR <= 0.48.
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Reasoning
Governing framework: ClinGen ENIGMA BRCA1/BRCA2 Specification v1.2 (cspec), BP5: 'Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data. BP5_VeryStrong - LR <=0.00285:1; BP5_Strong - LR <=0.05:1; BP5_Moderate - LR <=0.23:1; BP5 - LR <=0.48 to >0.23:1. Combined LR >0.48-1.00 is not informative (BP5 not applicable).' Note the operator for this criterion is the opposite direction to PS4/PP4: it strengthens as the value goes DOWN, and met requires combined clinical LR <= 0.48. The explicit inequality for this variant would be 'LR <= 0.48', but no LR value exists. The designated variant-level source PMID_31853058_BRCA2_clinical_history_LR.xlsx was searched for BRCA2 c.7141_7147dup and the protein notations p.Tyr2383SerfsTer11 / p.Y2383Sfs*11 - no row; nearest rows are the distinct substitutions c.7141C>G (LR 0.5045) and c.7147T>C (LR 0.8598), which are not this duplication (and would in any case fall outside the informative BP5 range). HUMU-40-1557-s001.xlsx (Parsons et al. 2019) and Easton et al. 2007 (PMID:17924331) contain no variant-specific entry. Separately, the variant is a truncating frameshift absent from gnomAD and ClinVar, and ENIGMA notes BP5 is N/A for co-observation with a second breast-ovarian cancer gene. No benign multifactorial clinical evidence exists. Conclusion: no LR value can be compared against <= 0.48, so BP5 is not assessed.
Rule
BP5 (ENIGMA BRCA2 v1.2): combined clinical LR <=0.48 (Supporting, >0.23), <=0.23 (Moderate), <=0.05 (Strong), <=0.00285 (Very Strong); LR >0.48-1.00 not informative. Low-supports-benign: met requires combined LR <= 0.48.
Evidence considered
ENIGMA BRCA2 v1.2 BP5 thresholds (cspec): BP5 LR <=0.48 to >0.23:1, Moderate <=0.23:1, Strong <=0.05:1, VeryStrong <=0.00285:1; combined LR >0.48-1.00 is not informative (BP5 not applicable). Low-supports-benign: met requires combined LR <= 0.48.
PMID_31853058_BRCA2_clinical_history_LR.xlsx searched for c.7141_7147dup / p.Tyr2383SerfsTer11 / p.Y2383Sfs*11 - no matching row; nearest rows c.7141C>G (LR 0.5045) and c.7147T>C (LR 0.8598) are different variants.
HUMU-40-1557-s001.xlsx (Parsons et al. 2019) searched for 7141/7147 and the protein change - no matching row.
Easton et al. 2007 (PMID:17924331) searched for 7141/7147/2383 - no variant-specific entry.
ENIGMA BP5 note: 'Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast-ovarian cancer risk genes have no specific phenotype'; no such co-observation data were collected for this variant in any case.
Still missing
PMID_31853058_BRCA2_clinical_history_LR.xlsx (the designated PP4/BP5 variant-level source) has no row for c.7141_7147dup; only the distinct substitutions c.7141C>G (LR 0.5045) and c.7147T>C (LR 0.8598) are present, so no combined clinical LR exists to test against the BP5 threshold (<= 0.48).
HUMU-40-1557-s001.xlsx (Parsons et al. 2019) and Easton et al. 2007 (PMID:17924331) contain no variant-specific multifactorial LR for this allele.
No co-occurrence/pathology/family-history clinical LR data exist for this frameshift; it is absent from ClinVar and gnomAD, so no benign clinical signal is available.
Not applicable · 15· recorded as not applicableShow reasons ▾Hide reasons ▴PS1N/ANot applicable: PS1 requires a predicted missense substitution or matched splice event, and this is a frameshift (p.Tyr2383SerfsTer11) with SpliceAI max delta 0.014.
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Reasoning
ENIGMA BRCA1/BRCA2 specification v1.2 (Table 1, STRONG CRITERIA, PS1_Variable Weight) restricts PS1 to two situations: (a) a variant predicted to lead to the SAME missense substitution as a known pathogenic/likely pathogenic variant caused by a different nucleotide change (with no confirmed or predicted mRNA splicing effect, SpliceAI <=0.1), or (b) exonic/intronic variants with the SAME predicted splicing event as a previously classified (likely) pathogenic variant, with the VUA's splice prediction required to be of similar or higher strength than that of the reference variant. NM_000059.4:c.7141_7147dup is a 7-nucleotide duplication that is out of frame and produces p.(Tyr2383SerfsTer11) - a protein-termination (frameshift) allele, not a predicted missense substitution, so branch (a) cannot be satisfied by construction. Branch (b) also fails: SpliceAI max delta score for this variant is 0.014 (DS_AG 0.002, DS_AL 0.005, DS_DG 0.001, DS_DL 0.014; Pangolin SG 0.011), i.e. no predicted splice impact, so there is no splice event to match against any reference variant. No comparator variant producing p.Tyr2383Ser or an equivalent splice event was found in any consulted VCEP file. The single nearby entry in the ENIGMA clinical-history likelihood-ratio table (PMID_31853058_BRCA2_clinical_history_LR.xlsx, row 'BRCA2 c.7141C>G') is a different nucleotide change at an adjacent codon and is a clinical-history LR row, not a PS1 reference variant; it was not used. PS1 is therefore unavailable for this variant type and is scored not applicable rather than not met.
Rule
ENIGMA BRCA2 v1.2 Table 1 PS1_Variable Weight - requires a predicted missense substitution identical to a known (likely) pathogenic variant, or an identical predicted splicing event; neither applies to an out-of-frame duplication.
Evidence considered
ENIGMA BRCA2 v1.2 Table 1 (PS1_Variable Weight): 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Also to be applied in the context of splicing predictions.' Application text limits PS1 to predicted missense substitutions (pathogenic reference: PS1; likely pathogenic reference: PS1_Moderate; both requiring no confirmed/predicted splice effect, SpliceAI <=0.1) and, separately, to exonic/intronic variants with the same predicted splicing impact as a previously classified (likely) pathogenic variant.
Variant identity: NM_000059.4:c.7141_7147dup (NC_000013.10:g.32929131_32929137dup), NP_000050.3:p.(Tyr2383SerfsTer11) / p.(Y2383Sfs*11) - a 7-bp duplication, out of frame.
SpliceAI lookup for NM_000059.4:c.7141_7147dup returned max delta score 0.014 (DS_DL 0.014 highest component), below the ENIGMA/SVI no-impact cutpoint of SpliceAI <=0.1, so no splice event exists that could be matched to a reference variant under the PS1 splicing branch.
Searched the declared VCEP full texts with grep for 'c.7141_7147dup', 'p.Tyr2383SerfsTer11', 'p.Y2383Sfs*11' and 'Y2383'/'Tyr2383': zero hits. The only '7141' hit anywhere in the VCEP corpus is the unrelated row BRCA2 c.7141C>G in PMID_31853058_BRCA2_clinical_history_LR.xlsx, which is a clinical-history LR entry and not a PS1 reference variant.
Still missing
No variant-specific PS1 reference entry exists for c.7141_7147dup or p.Tyr2383SerfsTer11 in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, Specifications_Table4_V1.2_2024-11-18.xlsx, Specifications_Table9_V1.2_2024-11-18.xlsx, SupplementaryTables_V1.2_2024-11-18.xlsx, or HUMU-40-1557-s001.xlsx - each was searched under all three notations and returned no row for this variant.
PS1 cannot be assessed at all for an out-of-frame duplication; a missense or splice-equivalent comparator would be required.
PS2VCEPNot applicable: ENIGMA BRCA2 v1.2 Table 1 explicitly directs 'Do not use' for PS2, as de novo occurrences are not calibrated for BRCA2.
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Reasoning
The governing framework for BRCA2 is the ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 v1.2. In Table 1 of Specifications_V1.2_2024-11-18.docx, PS2 is explicitly listed as 'Do not use', with the justification: 'BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.' This is a categorical prohibition on the code in this gene, not a threshold that could be met by any de novo observation. The same 'Do not use' directive appears in the structured CSPEC ruleset for this variant, where PS2 carries applicability 'Not Applicable'. Accordingly PS2 is not applicable for BRCA2 under ENIGMA v1.2, and no de novo evidence could make it met. Independently, the case evidence contains no proband/parental-testing data and no family-history or de novo occurrence information for c.7141_7147dup, so there is nothing that could be scored even under a generic framework.
VCEP rule
ENIGMA BRCA2 v1.2 (Table 1, PS2): Do not use — BRCA1/2-related cancers occur relatively commonly; no information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
ENIGMA BRCA2 v1.2 Table 1 (Specifications_V1.2_2024-11-18.docx) carries the entry PS2 with the application rule 'Do not use' and the stated basis: 'BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.'
The structured CSPEC record for this variant's gene/framework (doc 1535438831, ENIGMA BRCA1 and BRCA2 Specification v1.2) lists PS2 with applicability 'Not Applicable', consistent with Table 1.
The case evidence bundle contains no parental testing, no confirmed de novo occurrence, and no proband or family-history data for BRCA2 c.7141_7147dup; the case is a variant-level review.
Searched the case bundle files (review_manifest.json, case_summary.json, source_registry.json, evidence.json, literature_pass.json, fulltext_map.json, paper_extracts.json) for de novo/proband/parental keywords: no de novo observation is recorded for this variant.
PM1VCEPNot applicable: ENIGMA BRCA2 v1.2 Table 1 and Appendix J Table 16 both mark PM1 as 'do not use'/N/A, and residue 2383 is outside both defined domains (aa 10-40, aa 2481-3186).
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Reasoning
The governing ENIGMA BRCA1/BRCA2 specification v1.2 explicitly removes PM1 for BRCA2. Table 1 (MODERATE CRITERIA, PM1 row) states the criterion 'Located in a mutational hot spot and/or critical and well-established functional domain' is not used, with the application note 'Do not use. Considered as component of bioinformatic analysis (PP3/BP4).' Appendix J (Bioinformatic Analysis and Code Application, Table 16 'Overview of recommendations for bioinformatic and domain code weight application') repeats this: PM1 is 'N/A. Informed by clinically calibrated bioinformatic prior probability of pathogenicity for missense alterations - missense predictions only apply if a variant is located in a (potentially) clinically important functional domain. Evaluate under BP1, BP4, PP3.' The vcep_materials.json domain_tables key contains no entry for BRCA2 (empty object), so no authoritative extracted critical-domain list exists to test residue 2383 against; the only domain boundaries defined in the specification are for the bioinformatic codes (PP3/BP4/BP1): BRCA2 PALB2-binding domain aa 10-40 and BRCA2 DNA-binding domain aa 2481-3186, neither of which contains residue 2383. Independent of that, PM1 is a missense/domain criterion and this variant is a frameshift, and hotspot lookup (Cancer Hotspots, 'BRCA2 Y2383') returned no statistically significant hotspot. PM1 is therefore not applicable under the governing specification.
VCEP rule
ENIGMA BRCA2 v1.2 Table 1 PM1 = not used ('consider as component of bioinformatic analysis'); Appendix J Table 16 PM1 = N/A.
Evidence considered
ENIGMA BRCA2 v1.2 Table 1, PM1 row: 'Do not use. Considered as component of bioinformatic analysis (PP3/BP4).'
Appendices v1.2, Appendix J, Table 16: PM1 = 'N/A. Informed by clinically calibrated bioinformatic prior probability of pathogenicity for missense alterations - missense predictions only apply if a variant is located in a (potentially) clinically important functional domain. Evaluate under BP1, BP4, PP3.'
ENIGMA v1.2 domain definitions used by the bioinformatic codes (PP3/BP4/BP1): 'BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186'. Residue 2383 lies between these two domains, i.e. outside both.
vcep_materials.json domain_tables = {} (no BRCA2 entry), so no authoritative VCEP critical-domain table was available for a residue-membership test.
Hotspot query 'BRCA2 Y2383' (Cancer Hotspots) returned no row: this variant does not lie in a statistically significant hotspot.
Variant type is an out-of-frame 7-bp duplication (p.Tyr2383SerfsTer11), so no missense/domain mechanism can be invoked.
Still missing
vcep_materials.json has an empty domain_tables object for BRCA2, so there is no VCEP-extracted critical functional domain list to test residue 2383 against; the PM1 determination rests on the specification's explicit 'Do not use' rather than on a domain-membership test.
Searched Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx and Specifications_Table4_V1.2_2024-11-18.xlsx for a variant-level PM1 or hotspot entry for c.7141_7147dup / p.Tyr2383SerfsTer11 and found none; Table 4 carries no PM1 column (it covers PVS1 and PM5 (PTC) only).
PM2N/ANot applicable: the ENIGMA VCEP prohibits PM2 for insertion, deletion or delins variants, and this is a 7-bp duplication absent from gnomAD.
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Reasoning
The governing ENIGMA BRCA1/BRCA2 specification v1.2 states for PM2 explicitly: 'Do not apply for insertion, deletion or delins variants', and Appendix G explains why — PM2_Supporting is not recommended for insertion/deletion/indel variants because of low recall estimates for this variant class, with eligibility only for larger indels (> 50 bp) that are more reliably called. NM_000059.4:c.7141_7147dup is a 7-bp tandem duplication, i.e. an insertion-type variant well below the 50-bp exception, so PM2 is excluded by variant type irrespective of its absence from controls. For completeness, the frequency evidence would otherwise have supported PM2_Supporting: the variant is absent from the gnomAD v2.1 non-cancer exome subset and gnomAD v3.1 non-cancer genomes (the datasets the VCEP names for PM2), and from all-comers gnomAD v2.1 and v4.1. The criterion is therefore recorded as not_applicable rather than met, per the governing indel exclusion. No read-depth caveat (< 25) arises because the variant is not present in any dataset.
Rule
ENIGMA BRCA2 v1.2 PM2_Supporting: absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, read depth >= 25 — but NOT applicable to insertion/deletion/delins variants (indels <= 50 bp excluded).
Evidence considered
ENIGMA v1.2 PM2_Supporting rule: 'Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth >= 25.'
ENIGMA v1.2 PM2 instructionsToUse: 'Observation of a variant only once in a gnomAD outbred population is not informative... Do not apply for insertion, deletion or delins variants. Do not apply if read depth < 25 at region around the variant. Exclude data if variant failed quality control filter.'
Appendix G: 'We do not recommend use of PM2_Supporting for insertion, deletion or insertion-deletion variants due to the low recall estimates for variants of this type (Davidson et al 2021, PMID: 33600021). Larger insertions, deletions and indels (> 50bp) may be more reliably called and eligible for PM2_Supporting when absent from an appropriate dataset.'
Variant type: c.7141_7147dup is a 7-bp tandem duplication (mutalyzer normalized_model variant type 'duplication'), i.e. a small insertion-type allele, 7 bp — far below the > 50 bp threshold for the Appendix G exception.
gnomAD v2.1 non-cancer exome subset: absent. gnomAD v3.1 non-cancer genomes: absent. gnomAD v2.1 (all-comers) and gnomAD v4.1 (all-comers): absent. Had the variant class been eligible, this absence would have met PM2_Supporting (Appendix G LR 2.88, 95% CI 2.49-3.34, for absence from controls, supporting weight).
ClinVar: 'This variant is absent from ClinVar'; there are no submissions, so no population or co-occurrence data are borrowed from a curated record.
Still missing
PM2 is excluded for this variant class by the governing specification; the absence from gnomAD (FAF 0 across v2.1, v4.1, v2.1 non-cancer exomes and v3.1 non-cancer) is real but cannot be converted into a PM2 code for a duplication under ENIGMA v1.2.
No entry for c.7141_7147dup, p.Tyr2383SerfsTer11 or p.Y2383Sfs*11 was found in any declared VCEP file searched in full text (Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, HUMU-40-1557-s001.xlsx, SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_Table4_V1.2_2024-11-18.xlsx, Specifications_Table9_V1.2_2024-11-18.xlsx); no pre-assigned PM2 code exists for this variant.
gnomAD-Canada v1.0 was unreachable (connection reset by peer) and is not part of the ENIGMA PM2 dataset definition (gnomAD v2.1 non-cancer exomes; gnomAD v3.1 non-cancer genomes); this does not affect the assessment.
PM4VCEPNot applicable: ENIGMA BRCA2 v1.2 lists PM4 as 'Do not use', and this frameshift produces a premature stop, not an in-frame protein length change.
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Reasoning
PM4 (protein length change due to in-frame deletion/insertion in a non-repeat region, or stop-loss variant) is explicitly disabled for BRCA2 by the governing ENIGMA BRCA1/BRCA2 VCEP specification v1.2: the Table 1 entry for PM4 reads 'Do not use - Considered as component of bioinformatic analysis (PP3/BP4)'. In addition, the variant is not of the type PM4 describes: c.7141_7147dup is a 7-bp duplication that shifts the reading frame (p.Tyr2383SerfsTer11) and produces a premature termination codon rather than an in-frame length change, and it is not a stop-loss variant. Its protein-length consequence is captured under PVS1 (with the exon-14 PTC weight from Table 4) and, for bioinformatic prediction, under the PP3/BP4 pathway, not PM4. PM4 is therefore not applicable to this variant under the governing BRCA2 framework.
VCEP rule
ENIGMA BRCA1/BRCA2 VCEP v1.2, Table 1: PM4 - Do not use (considered as a component of bioinformatic analysis PP3/BP4).
Evidence considered
ENIGMA BRCA1/BRCA2 VCEP specification v1.2, Table 1 (MODERATE CRITERIA, PM4): 'Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.' Specification column: 'Do not use - Considered as component of bioinformatic analysis (PP3/BP4).'
Case variant record: NM_000059.4:c.7141_7147dup, NP_000050.3:p.(Y2383Sfs*11), consequence_class frameshift - a frameshift with a downstream PTC, not an in-frame indel or stop-loss, so the variant type PM4 addresses is absent.
Still missing
No PM4-specific VCEP row for this variant exists because the ENIGMA BRCA1/BRCA2 VCEP disables PM4 entirely; no further PM4 evidence was sought.
Searched Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt and Specifications_Table4_V1.2_2024-11-18.xlsx.txt for c.7141_7147dup / p.Tyr2383SerfsTer11 / p.Y2383Sfs*11: the variant is not named in these files.
PM6VCEPNot applicable: ENIGMA BRCA2 v1.2 Table 1 explicitly directs 'Do not use' for PM6, as de novo occurrences are not calibrated for BRCA2.
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Reasoning
Under the governing ENIGMA BRCA2 v1.2 specification, PM6 is explicitly listed as 'Do not use'. Table 1 of Specifications_V1.2_2024-11-18.docx states for PM6: 'BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.' The structured CSPEC record for this framework likewise assigns PM6 applicability 'Not Applicable'. Because the code is categorically disallowed for BRCA2, no assumed-de-novo observation could satisfy it. Separately and independently, the case evidence records no proband, no parental genotypes, and no assumed de novo event for c.7141_7147dup, so there is no candidate event to score.
VCEP rule
ENIGMA BRCA2 v1.2 (Table 1, PM6): Do not use — BRCA1/2-related cancers occur relatively commonly; no information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
ENIGMA BRCA2 v1.2 Table 1 (Specifications_V1.2_2024-11-18.docx) carries the entry PM6 with the application rule 'Do not use' and the stated basis: 'BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.'
The structured CSPEC record for the ENIGMA BRCA1 and BRCA2 Specification v1.2 (doc 1535438831) lists PM6 with applicability 'Not Applicable'.
No parental testing, no assumed/confirmed de novo event, and no family data are present in the case evidence for BRCA2 c.7141_7147dup.
PP2VCEPNot applicable: ENIGMA BRCA2 v1.2 marks PP2 'do not use' because missense change is not a common BRCA2 mechanism, and this variant is a frameshift, not missense.
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Reasoning
PP2 ('missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease') is explicitly withdrawn for BRCA2 in the governing specification. ENIGMA BRCA1/BRCA2 v1.2 Table 1, PP2 row: 'Do not use. High frequency of benign missense variants.' Appendix J Table 16 gives the same determination with the reason: 'PP2 Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - N/A. Missense variants are not a common mechanism of pathogenicity for BRCA1 and BRCA2.' The criterion is in any case a missense-specific criterion, and NM_000059.4:c.7141_7147dup produces a frameshift protein-termination allele (p.Tyr2383SerfsTer11) rather than a missense substitution. PP2 is therefore not applicable under the governing VCEP framework and is scored as such rather than as not met.
ENIGMA BRCA2 v1.2 Table 1, PP2 row: 'Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease' - 'Do not use. High frequency of benign missense variants.'
Appendices v1.2, Appendix J Table 16: PP2 = 'N/A. Missense variants are not a common mechanism of pathogenicity for BRCA1 and BRCA2.'
Variant type is an out-of-frame 7-bp duplication with consequence p.(Tyr2383SerfsTer11), not a missense substitution, so the criterion's own precondition is unmet as well.
Still missing
No PP2 entry for c.7141_7147dup or p.Tyr2383SerfsTer11 exists in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx or the extracted VCEP tables; PP2 is a gene-level missense-mechanism criterion that the VCEP has withdrawn, so no variant-level evidence search could change the outcome.
PP3N/ANot applicable: PP3 covers missense, in-frame and splice-region variants, while c.7141_7147dup is a frameshift PTC (p.Tyr2383SerfsTer11), so its impact belongs to PVS1.
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Reasoning
NM_000059.4:c.7141_7147dup is a 7-bp duplication that produces a frameshift with a premature termination codon (NP_000050.3:p.(Tyr2383SerfsTer11)); the variant is classified as frameshift/truncating, not missense, in-frame, silent or intronic. The governing ENIGMA BRCA2 specification v1.2 (Table 1, Table 16, Appendix J) defines exactly two PP3 paths: (1) missense or in-frame insertion/deletion/delins inside a (potentially) clinically important functional domain with a predicted protein impact (BayesDel no-AF >= 0.30 for BRCA2), and (2) predicted splice impact via SpliceAI >= 0.2, which is explicitly limited to silent, missense/in-frame and intronic variants outside the donor/acceptor +/-1,2 positions. A frameshift/PTC variant falls outside both paths, so PP3 is out of scope at the level of variant class, before any predictor score is considered. The specification reinforces this by stating 'Do not apply PP3 if PVS1 is met at any strength', i.e. PP3 is reserved for non-truncating mechanisms; the functional consequence of this variant is captured by the PVS1/PTC path instead. The SpliceAI max delta score present for this variant (0.014) was therefore not evaluated as PP3 evidence, and no mis-sense predictor score (BayesDel/REVEL) exists or is applicable. No VCEP file pre-assigns a PP3 code for this variant, so nothing overrides the scope determination.
Rule
ENIGMA BRCA2 Specifications v1.2, Table 1 (PP3 row) and Appendix J / Table 16: PP3 applies only to missense or in-frame indels inside a (potentially) clinically important functional domain (BayesDel no-AF >= 0.30 for BRCA2) or to predicted splice impact (SpliceAI >= 0.2) for silent, missense/in-frame and intronic variants outside donor/acceptor +/-1,2 positions; do not apply PP3 if PVS1 is met at any strength.
Evidence considered
Scope check performed before any predictor score: normalization gives NM_000059.4:c.7141_7147dup -> NP_000050.3:p.(Y2383SerfsTer11) / p.(Tyr2383Serfs*11), and the PVS1 variant assessment records consequence_class 'frameshift' with variant_bucket 'frameshift' and a premature termination codon.
ENIGMA BRCA2 specification v1.2 (Table 1 PP3 row): 'Do not apply PP3 if PVS1 is met at any strength. Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel predicted Impact). Apply PP3 for predicted splicing (SpliceAI >=0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor +/-1,2 positions.'
Appendix J, Table 16 (Overview of recommendations for bioinformatic and domain code weight application): the PP3 row lists only missense/in-frame indels inside a (potentially) clinically important functional domain (BayesDel >= 0.28 BRCA1, >= 0.30 BRCA2) and SpliceAI >= 0.2 for silent, missense/in-frame and intronic variants; no truncating/frameshift class is listed in either PP3 path.
Appendix J calibration section: the optimal SpliceAI cutpoints '<=0.1 for BP4', '>0.1 and <0.2 not informative' and '>=0.2 for PP3' were derived for variants outside the donor/acceptor +/-1,2 positions; the PP3 splice path is therefore a splice-region path, not a truncating-variant path.
The SpliceAI score reported in the case evidence (max delta score 0.014) was not used for PP3, because a frameshift variant is outside the scope of the PP3 splice path; this avoids applying a computational criterion to a variant class it was not calibrated for.
No pre-assigned PP3 code was found in any declared VCEP file (searched Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, Specifications_Table4/9, SupplementaryTables and HUMU-40-1557-s001 for c.7141_7147dup, p.Tyr2383SerfsTer11 and p.Y2383Sfs*11).
BayesDel and REVEL scores are absent for this variant (BayesDel score null, REVEL score null); in any case neither predictor applies to a frameshift, so no missense in-silico path is available or needed.
Still missing
Searched the full text of the declared VCEP files Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx and PMID_22505045_Houdayer_2012_HumMutat.pdf for c.7141_7147dup, p.Tyr2383SerfsTer11 and p.Y2383Sfs*11: no variant-level or class-level PP3 entry exists for this variant. This is not an evidence gap affecting the verdict, because PP3 is out of scope by variant class (frameshift/truncating).
PP5VCEPNot applicable: ENIGMA declares PP5 not applicable for BRCA2, and the variant has no ClinVar expert-panel classification (absent from ClinVar).
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Reasoning
Governing framework: the ENIGMA BRCA1/BRCA2 Specification v1.2 (cspec) lists PP5 with applicability 'Not Applicable' for BRCA2. Independently of the VCEP declaration, PP5 requires an exact-variant ClinVar expert-panel (VCEP/ClinGen) classification of Pathogenic or Likely pathogenic; only such an expert-panel assertion may trigger PP5, and ordinary laboratory submissions or aggregate labels must not. ClinVar was searched with multiple exact terms (BRCA2[GENE] AND c.7141_7147dup[VARNAME]; NM_000059.4:c.7141_7147dup; NC_000013.10:g.32929131_32929137dup); exact_match=false and 'This variant is absent from ClinVar.' There is therefore no ClinVar record, expert-panel or otherwise, for this variant. The trigger condition for PP5 is not satisfied and the VCEP framework itself does not use PP5. Conclusion: PP5 not applicable.
VCEP rule
PP5 requires an exact-variant ClinVar expert-panel classification of Pathogenic/Likely pathogenic. ENIGMA BRCA2 v1.2 declares PP5 Not Applicable; ClinVar has no record for this variant.
ClinVar: exact_match=false; variation_ids empty; 'This variant is absent from ClinVar.' No expert-panel classification exists, so the PP5 trigger condition (exact-variant Pathogenic/Likely pathogenic expert-panel assertion) cannot be met.
BP1N/ANot applicable: ENIGMA BP1_Strong is limited to silent, missense or in-frame indels outside functional domains, and this is an out-of-frame 7-bp duplication.
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Reasoning
Under ENIGMA BRCA2 v1.2 the BP1 code is applied only as BP1_Strong, and the specification restricts it by variant type. Table 1 (SUPPORTING CRITERIA, BP1_Strong) states: 'Apply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI <=0.1). Missense prediction not applicable.' NM_000059.4:c.7141_7147dup is a 7-nucleotide out-of-frame duplication (p.(Tyr2383SerfsTer11)); it is not a silent substitution, not a missense variant and not an in-frame insertion/deletion/delins, so the criterion's variant-type precondition fails and BP1 cannot be applied at any strength. The other two limbs of the rule were nevertheless checked and would in isolation point the same way as the framework expects for such positions: residue 2383 lies outside both BRCA2 (potentially) clinically important functional domains defined in the specification (PALB2-binding domain aa 10-40; DNA-binding domain aa 2481-3186), and SpliceAI max delta for this variant is 0.014, i.e. <=0.1, so no splicing is predicted. Because BP1 is defined solely for the listed variant types, the correct outcome is not applicable rather than not met. (Appendix J confirms the location-based benign information for exonic variants is delivered through the bioinformatic codes rather than BP1 for non-missense/non-in-frame alleles.)
Rule
ENIGMA BRCA2 v1.2 Table 1 BP1_Strong - restricted to silent substitution, missense or in-frame insertion/deletion/delins variants outside a (potentially) clinically important functional domain with SpliceAI <=0.1; variant-type precondition fails for an out-of-frame duplication.
Evidence considered
ENIGMA BRCA2 v1.2 Table 1, BP1_Strong row: 'Apply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI <=0.1). Missense prediction not applicable.'
(Potentially) clinically important functional domains per the same specification: 'BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186'. Residue 2383 is outside both, but BP1's variant-type gate is dispositive for an out-of-frame duplication.
SpliceAI lookup for NM_000059.4:c.7141_7147dup: max delta score 0.014 (<=0.1), i.e. no predicted splicing impact - this satisfies only the splice limb of the BP1 rule.
Appendix J Table 16 confirms BP1 for BRCA2 is 'informed by clinically calibrated bioinformatic prior probability of pathogenicity, that considers functional domain, missense/in-frame changes, splicing effects', i.e. it is a location/prediction code for missense and in-frame alleles, which this frameshift allele is not.
Still missing
BP1 has no entry for c.7141_7147dup or p.Tyr2383SerfsTer11 in Specifications_V1.2_2024-11-18.docx or Appendices_V1.2_2024-11-18.docx (both searched); the criterion is excluded by variant type, so no further source could change the verdict.
The domain-location and SpliceAI limbs of the BP1 rule were verified for completeness (residue 2383 outside aa 10-40 and aa 2481-3186; SpliceAI max delta 0.014), but they are not decisive because the variant-type gate already fails.
BP2VCEPNot applicable: the ENIGMA v1.2 specification explicitly bars BP2 for BRCA2, allowing it only within the gene-specific BS2 co-occurrence framework.
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Reasoning
Governing framework: ClinGen ENIGMA BRCA1/BRCA2 specification v1.2 Table 1 lists BP2 with the explicit instruction 'Do not use; applied only in the context of BS2', and the CSPEC rule set records BP2 as applicability 'Not applicable' with empty strength rules at every level. The cis/trans co-occurrence information that the generic ACMG/AMP BP2 code would otherwise capture is deliberately absorbed into the gene-specific BS2 point framework (Table 8 / Appendix H Table 13), not into BP2. In this case the factual predicate is also absent: no variant is reported in cis with a pathogenic variant in BRCA2 or in trans in a trans-configuration usable under this specification, and no phase information is available at all for c.7141_7147dup. Because the governing specification removes BP2 from use for BRCA2, the code cannot be applied at any strength in either direction.
VCEP rule
ENIGMA BRCA1/BRCA2 specification v1.2, Table 1, BP2 row: 'Do not use. Applied only in the context of BS2.' -> not applicable for BRCA2 variant interpretation.
Evidence considered
ENIGMA BRCA1/BRCA2 specification v1.2 Table 1 (BP2 row): 'Do not use. Applied only in the context of BS2.' The specification therefore assigns no BRCA2-specific BP2 rule and the code is unavailable for this gene.
CSPEC rule set for this gene records the BP2 code with applicability 'Not applicable' and no strength rules populated for Stand Alone, Very Strong, Strong, Moderate or Supporting, confirming BP2 cannot be applied at any weight.
The class of evidence that BP2 would capture (co-occurrence with a pathogenic variant in cis, or in trans for a fully penetrant dominant disorder) is instead handled by the gene-specific BS2 point system (Specification Table 8 and Appendix H Table 13), which is outside this group's criteria.
No cis or trans configuration is documented for c.7141_7147dup: no parental/offspring genotyping, no phasing, and no co-occurring pathogenic BRCA2 variant is reported anywhere in the case evidence.
All five retrieved full texts (PMID:10570174, PMID:11239455, PMID:20878484, PMID:22193408, PMID:24312913) were searched for the variant under coding and protein notations; none reports it and none provides a cis/trans co-occurrence observation for it.
Still missing
No cis/trans phase information (parental genotyping, segregation of the two alleles, or a co-occurring pathogenic variant) is present for c.7141_7147dup in the case evidence, but this is moot because the governing specification does not permit BP2 to be applied for BRCA2.
Searched Specifications_V1.2_2024-11-18.docx and all other on-record BRCA2 VCEP files for 'c.7141_7147dup', 'p.Tyr2383SerfsTer11' and 'p.Y2383Sfs*11': no variant-specific BP2 entry exists, consistent with BP2 being listed as not applicable by the specification.
BP3VCEPNot applicable: ENIGMA BRCA2 v1.2 lists BP3 as 'Do not use', and this frameshift is not an in-frame insertion or deletion in a repeat region.
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Reasoning
BP3 (in-frame deletion/insertion in a repetitive region without a known function) is explicitly disabled for BRCA2 by the governing ENIGMA BRCA1/BRCA2 VCEP specification v1.2: the Table 1 entry for BP3 reads 'Do not use - Captured by bioinformatic tool prediction, and domain analysis. See Appendix J.' The variant is also not of the type BP3 describes: c.7141_7147dup is a 7-bp duplication that shifts the reading frame (p.Tyr2383SerfsTer11) and introduces a premature termination codon, so it is not an in-frame insertion or deletion in a repetitive region. The repetitive-region/in-frame consequence space BP3 covers is instead handled within the ENIGMA bioinformatic pathway. BP3 is therefore not applicable to this variant under the governing BRCA2 framework.
VCEP rule
ENIGMA BRCA1/BRCA2 VCEP v1.2, Table 1: BP3 - Do not use (captured by bioinformatic tool prediction and domain analysis; Appendix J).
Evidence considered
ENIGMA BRCA1/BRCA2 VCEP specification v1.2, Table 1 (SUPPORTING CRITERIA, BP3): 'In-frame deletions/insertions in a repetitive region without a known function.' Specification column: 'Do not use - Captured by bioinformatic tool prediction, and domain analysis. See Appendix J.'
Case variant record: NM_000059.4:c.7141_7147dup, NP_000050.3:p.(Y2383Sfs*11), consequence_class frameshift - an out-of-frame duplication producing a PTC, not an in-frame change in a repeat region, so the variant type BP3 addresses is absent.
Still missing
No BP3-specific VCEP row for this variant exists because the ENIGMA BRCA1/BRCA2 VCEP disables BP3 entirely; no further BP3 evidence was sought.
Searched Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt and Specifications_Table4_V1.2_2024-11-18.xlsx.txt for c.7141_7147dup / p.Tyr2383SerfsTer11 / p.Y2383Sfs*11: the variant is not named in these files.
BP4N/ANot applicable: BP4 covers missense, in-frame, silent and intronic variants, while c.7141_7147dup is a frameshift PTC, so its low SpliceAI score was not used.
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Reasoning
NM_000059.4:c.7141_7147dup is a frameshift duplication with a premature termination codon (NP_000050.3:p.(Tyr2383SerfsTer11)), not a missense, in-frame, silent or intronic variant. The governing ENIGMA BRCA2 specification v1.2 defines BP4 for three variant classes only: (1) missense or in-frame insertion/deletion/delins inside a (potentially) clinically important functional domain with no predicted protein or splice impact (BayesDel no-AF <= 0.18 for BRCA2 AND SpliceAI <= 0.1); (2) silent variants inside such a domain with SpliceAI <= 0.1; and (3) intronic variants outside the donor/acceptor +/-1,2 positions with SpliceAI <= 0.1. A truncating frameshift is in none of these classes, so BP4 is out of scope upstream of any predictor value. Consequently the SpliceAI max delta score available for this variant (0.014) was not evaluated as BP4 evidence even though it is numerically below the 0.1 threshold; the variant's effect is governed by the PVS1/PTC path. No VCEP file pre-assigns a BP4 code for this variant.
Rule
ENIGMA BRCA2 Specifications v1.2, Table 1 (BP4 row) and Appendix J / Table 16: BP4 applies only to missense or in-frame indels inside a (potentially) clinically important functional domain with BayesDel no-AF <= 0.18 and SpliceAI <= 0.1, to silent variants inside such a domain with SpliceAI <= 0.1, or to intronic variants outside donor/acceptor +/-1,2 positions with SpliceAI <= 0.1.
Evidence considered
Scope check performed before any predictor score: the variant is a 7-bp duplication causing a frameshift with a premature termination codon (p.(Tyr2383SerfsTer11)); the PVS1 variant assessment records consequence_class 'frameshift' and variant_bucket 'frameshift'.
ENIGMA BRCA2 specification v1.2 (Table 1 BP4 row): 'Apply BP4 for: Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel predicted No Impact AND SpliceAI <= 0.1). Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI <= 0.1). Intronic variants outside of the donor and acceptor +/-1,2 positions AND no predicted impact via splicing (SpliceAI <= 0.1).'
Appendix J, Table 16 (BP4 row): the same three variant classes are listed (missense/in-frame inside domain with BayesDel <= 0.15 BRCA1 / <= 0.18 BRCA2 and SpliceAI <= 0.1; silent inside domain with SpliceAI <= 0.1; intronic outside +/-1,2 with SpliceAI <= 0.1). No truncating/frameshift class is included.
The SpliceAI max delta score for this variant (0.014, i.e. below the 0.1 cutpoint) was deliberately not applied as BP4, because the BP4 splicing path is restricted to silent, missense/in-frame and intronic variants and this variant is a frameshift.
No pre-assigned BP4 code was found in any declared VCEP file (searched Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, Specifications_Table4/9, SupplementaryTables and HUMU-40-1557-s001 for c.7141_7147dup, p.Tyr2383SerfsTer11 and p.Y2383Sfs*11).
Still missing
Searched the full text of Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx and PMID_22505045_Houdayer_2012_HumMutat.pdf for c.7141_7147dup, p.Tyr2383SerfsTer11 and p.Y2383Sfs*11: no variant-level or class-level BP4 entry exists for this variant. This is not an evidence gap affecting the verdict, because BP4 is out of scope by variant class (frameshift/truncating).
BP6VCEPNot applicable: ENIGMA declares BP6 not applicable for BRCA2, and the variant is absent from ClinVar with no expert-panel assertion.
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Reasoning
Governing framework: the ENIGMA BRCA1/BRCA2 Specification v1.2 (cspec) lists BP6 with applicability 'Not Applicable' for BRCA2. Independently of the VCEP declaration, BP6 requires an exact-variant ClinVar expert-panel (VCEP/ClinGen) classification of Benign or Likely benign; only such an expert-panel assertion may trigger BP6, and ordinary laboratory submissions or aggregate labels must not. ClinVar was searched with multiple exact terms (BRCA2[GENE] AND c.7141_7147dup[VARNAME]; NM_000059.4:c.7141_7147dup; NC_000013.10:g.32929131_32929137dup) and returned no record (exact_match=false; 'This variant is absent from ClinVar'). There is no ClinVar expert-panel assertion for this variant, so the trigger condition for BP6 is not satisfied and the VCEP framework itself does not use BP6. Conclusion: BP6 not applicable.
VCEP rule
BP6 requires an exact-variant ClinVar expert-panel classification of Benign/Likely benign. ENIGMA BRCA2 v1.2 declares BP6 Not Applicable; ClinVar has no record for this variant.
ClinVar: exact_match=false; variation_ids empty; 'This variant is absent from ClinVar.' No expert-panel classification exists, so the BP6 trigger condition (exact-variant Benign/Likely benign expert-panel assertion) cannot be met.
BP7N/ANot applicable: BP7 applies only to synonymous (or deep-intronic) variants, and c.7141_7147dup is a frameshift PTC (p.Tyr2383SerfsTer11).
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Reasoning
NM_000059.4:c.7141_7147dup is a frameshift duplication producing a premature termination codon (NP_000050.3:p.(Tyr2383SerfsTer11)), not a synonymous variant and not an intronic variant. The governing ENIGMA BRCA2 specification v1.2 applies BP7 (i) to a synonymous (silent) variant with no predicted splicing impact, inside a (potentially) clinically important functional domain, where BP4 is met, and (ii) as an extension, to intronic variants located outside the conserved donor/acceptor motif positions (at or beyond +7/-21) where BP4 is met; a separate BP7_Strong (RNA) repurposing applies to well-established mRNA assays showing no aberrant transcript. None of these classes covers a frameshift/PTC variant, so BP7 is out of scope upstream of any predictor value, and the SpliceAI max delta score available for this variant (0.014) was not evaluated. No VCEP file pre-assigns a BP7 code for this variant.
Rule
ENIGMA BRCA2 Specifications v1.2, Table 1 (BP7 row) and Appendix J / Table 16: BP7 applies to a synonymous variant inside a (potentially) clinically important functional domain where BP4 is met, and (extension) to intronic variants at or beyond +7/-21 positions where BP4 is met; BP7_Strong (RNA) applies to mRNA assay evidence of no damaging effect in intronic/silent/missense-in-frame variants outside a clinically important domain.
Evidence considered
Scope check performed before any predictor score: the variant is a frameshift duplication with a premature termination codon (p.(Tyr2383SerfsTer11)) and is not synonymous; the PVS1 variant assessment records consequence_class 'frameshift'.
ENIGMA BRCA2 specification v1.2 (Table 1 BP7 row): 'Apply BP7 for Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.'
Appendix J, Table 16 (BP7 row): 'Following convention, this code is applied in addition to BP4 (no splicing prediction, Splice AI <= 0.1) to capture the low prior probability of pathogenicity of silent variants. Nucleotide conservation is not considered relevant. Apply BP7 for silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (BP4 met). Also apply BP7 for intronic variants located outside of conserved donor or acceptor motif positions (at or beyond positions +7/-21), if no predicted impact via splicing (BP4 met).'
Appendix E/Figure 9 context: the BP7_Strong (RNA) repurposing applies to intronic, silent and missense/in-frame variants outside a (potentially) clinically important functional domain on the basis of mRNA assay results showing no damaging effect; it likewise does not cover truncating frameshift variants.
The SpliceAI max delta score for this variant (0.014) was not used for BP7, since BP7 is defined for synonymous (and deep-intronic) variants and this variant is a frameshift.
No pre-assigned BP7 code was found in any declared VCEP file (searched Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, Specifications_Table4/9, SupplementaryTables and HUMU-40-1557-s001 for c.7141_7147dup, p.Tyr2383SerfsTer11 and p.Y2383Sfs*11).
Still missing
Searched the full text of Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx and PMID_22505045_Houdayer_2012_HumMutat.pdf for c.7141_7147dup, p.Tyr2383SerfsTer11 and p.Y2383Sfs*11: no variant-level or class-level BP7 entry exists for this variant. This is not an evidence gap affecting the verdict, because BP7 is out of scope by variant class (frameshift/truncating, not synonymous).
Every interpreted variant in BRCA2, mapped onto the exon structure of NM_000059.4. Select a row to find it on the plot.
BRCA2NM_000059.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in BRCA2—Select a row to find it on the plot; use the link to open its page.
Protein
Location
Classification
Link
gnomAD v4.1Allele count data not recorded
gnomAD v2.1Allele count data not recorded
gnomAD-Canada v1.0Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -131 bp
0.005
SpliceAI acceptor gainat +115 bp
0.002
SpliceAI donor lossat +301 bp
0.014
SpliceAI donor gainat +391 bp
0.001
Pangolin splice lossmagnitude shown
-0.062
Pangolin splice gain
0.011
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3N/ANot applicable: PP3 covers missense, in-frame and splice-region variants, while c.7141_7147dup is a frameshift PTC (p.Tyr2383SerfsTer11), so its impact belongs to PVS1.
Details ▾Hide ▴
Reasoning
NM_000059.4:c.7141_7147dup is a 7-bp duplication that produces a frameshift with a premature termination codon (NP_000050.3:p.(Tyr2383SerfsTer11)); the variant is classified as frameshift/truncating, not missense, in-frame, silent or intronic. The governing ENIGMA BRCA2 specification v1.2 (Table 1, Table 16, Appendix J) defines exactly two PP3 paths: (1) missense or in-frame insertion/deletion/delins inside a (potentially) clinically important functional domain with a predicted protein impact (BayesDel no-AF >= 0.30 for BRCA2), and (2) predicted splice impact via SpliceAI >= 0.2, which is explicitly limited to silent, missense/in-frame and intronic variants outside the donor/acceptor +/-1,2 positions. A frameshift/PTC variant falls outside both paths, so PP3 is out of scope at the level of variant class, before any predictor score is considered. The specification reinforces this by stating 'Do not apply PP3 if PVS1 is met at any strength', i.e. PP3 is reserved for non-truncating mechanisms; the functional consequence of this variant is captured by the PVS1/PTC path instead. The SpliceAI max delta score present for this variant (0.014) was therefore not evaluated as PP3 evidence, and no mis-sense predictor score (BayesDel/REVEL) exists or is applicable. No VCEP file pre-assigns a PP3 code for this variant, so nothing overrides the scope determination.
Rule
ENIGMA BRCA2 Specifications v1.2, Table 1 (PP3 row) and Appendix J / Table 16: PP3 applies only to missense or in-frame indels inside a (potentially) clinically important functional domain (BayesDel no-AF >= 0.30 for BRCA2) or to predicted splice impact (SpliceAI >= 0.2) for silent, missense/in-frame and intronic variants outside donor/acceptor +/-1,2 positions; do not apply PP3 if PVS1 is met at any strength.
Evidence considered
Scope check performed before any predictor score: normalization gives NM_000059.4:c.7141_7147dup -> NP_000050.3:p.(Y2383SerfsTer11) / p.(Tyr2383Serfs*11), and the PVS1 variant assessment records consequence_class 'frameshift' with variant_bucket 'frameshift' and a premature termination codon.
ENIGMA BRCA2 specification v1.2 (Table 1 PP3 row): 'Do not apply PP3 if PVS1 is met at any strength. Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel predicted Impact). Apply PP3 for predicted splicing (SpliceAI >=0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor +/-1,2 positions.'
Appendix J, Table 16 (Overview of recommendations for bioinformatic and domain code weight application): the PP3 row lists only missense/in-frame indels inside a (potentially) clinically important functional domain (BayesDel >= 0.28 BRCA1, >= 0.30 BRCA2) and SpliceAI >= 0.2 for silent, missense/in-frame and intronic variants; no truncating/frameshift class is listed in either PP3 path.
Appendix J calibration section: the optimal SpliceAI cutpoints '<=0.1 for BP4', '>0.1 and <0.2 not informative' and '>=0.2 for PP3' were derived for variants outside the donor/acceptor +/-1,2 positions; the PP3 splice path is therefore a splice-region path, not a truncating-variant path.
The SpliceAI score reported in the case evidence (max delta score 0.014) was not used for PP3, because a frameshift variant is outside the scope of the PP3 splice path; this avoids applying a computational criterion to a variant class it was not calibrated for.
No pre-assigned PP3 code was found in any declared VCEP file (searched Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, Specifications_Table4/9, SupplementaryTables and HUMU-40-1557-s001 for c.7141_7147dup, p.Tyr2383SerfsTer11 and p.Y2383Sfs*11).
BayesDel and REVEL scores are absent for this variant (BayesDel score null, REVEL score null); in any case neither predictor applies to a frameshift, so no missense in-silico path is available or needed.
Still missing
Searched the full text of the declared VCEP files Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx and PMID_22505045_Houdayer_2012_HumMutat.pdf for c.7141_7147dup, p.Tyr2383SerfsTer11 and p.Y2383Sfs*11: no variant-level or class-level PP3 entry exists for this variant. This is not an evidence gap affecting the verdict, because PP3 is out of scope by variant class (frameshift/truncating).
BP4N/ANot applicable: BP4 covers missense, in-frame, silent and intronic variants, while c.7141_7147dup is a frameshift PTC, so its low SpliceAI score was not used.
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Reasoning
NM_000059.4:c.7141_7147dup is a frameshift duplication with a premature termination codon (NP_000050.3:p.(Tyr2383SerfsTer11)), not a missense, in-frame, silent or intronic variant. The governing ENIGMA BRCA2 specification v1.2 defines BP4 for three variant classes only: (1) missense or in-frame insertion/deletion/delins inside a (potentially) clinically important functional domain with no predicted protein or splice impact (BayesDel no-AF <= 0.18 for BRCA2 AND SpliceAI <= 0.1); (2) silent variants inside such a domain with SpliceAI <= 0.1; and (3) intronic variants outside the donor/acceptor +/-1,2 positions with SpliceAI <= 0.1. A truncating frameshift is in none of these classes, so BP4 is out of scope upstream of any predictor value. Consequently the SpliceAI max delta score available for this variant (0.014) was not evaluated as BP4 evidence even though it is numerically below the 0.1 threshold; the variant's effect is governed by the PVS1/PTC path. No VCEP file pre-assigns a BP4 code for this variant.
Rule
ENIGMA BRCA2 Specifications v1.2, Table 1 (BP4 row) and Appendix J / Table 16: BP4 applies only to missense or in-frame indels inside a (potentially) clinically important functional domain with BayesDel no-AF <= 0.18 and SpliceAI <= 0.1, to silent variants inside such a domain with SpliceAI <= 0.1, or to intronic variants outside donor/acceptor +/-1,2 positions with SpliceAI <= 0.1.
Evidence considered
Scope check performed before any predictor score: the variant is a 7-bp duplication causing a frameshift with a premature termination codon (p.(Tyr2383SerfsTer11)); the PVS1 variant assessment records consequence_class 'frameshift' and variant_bucket 'frameshift'.
ENIGMA BRCA2 specification v1.2 (Table 1 BP4 row): 'Apply BP4 for: Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel predicted No Impact AND SpliceAI <= 0.1). Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI <= 0.1). Intronic variants outside of the donor and acceptor +/-1,2 positions AND no predicted impact via splicing (SpliceAI <= 0.1).'
Appendix J, Table 16 (BP4 row): the same three variant classes are listed (missense/in-frame inside domain with BayesDel <= 0.15 BRCA1 / <= 0.18 BRCA2 and SpliceAI <= 0.1; silent inside domain with SpliceAI <= 0.1; intronic outside +/-1,2 with SpliceAI <= 0.1). No truncating/frameshift class is included.
The SpliceAI max delta score for this variant (0.014, i.e. below the 0.1 cutpoint) was deliberately not applied as BP4, because the BP4 splicing path is restricted to silent, missense/in-frame and intronic variants and this variant is a frameshift.
No pre-assigned BP4 code was found in any declared VCEP file (searched Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, Specifications_Table4/9, SupplementaryTables and HUMU-40-1557-s001 for c.7141_7147dup, p.Tyr2383SerfsTer11 and p.Y2383Sfs*11).
Still missing
Searched the full text of Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx and PMID_22505045_Houdayer_2012_HumMutat.pdf for c.7141_7147dup, p.Tyr2383SerfsTer11 and p.Y2383Sfs*11: no variant-level or class-level BP4 entry exists for this variant. This is not an evidence gap affecting the verdict, because BP4 is out of scope by variant class (frameshift/truncating).
BP7N/ANot applicable: BP7 applies only to synonymous (or deep-intronic) variants, and c.7141_7147dup is a frameshift PTC (p.Tyr2383SerfsTer11).
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Reasoning
NM_000059.4:c.7141_7147dup is a frameshift duplication producing a premature termination codon (NP_000050.3:p.(Tyr2383SerfsTer11)), not a synonymous variant and not an intronic variant. The governing ENIGMA BRCA2 specification v1.2 applies BP7 (i) to a synonymous (silent) variant with no predicted splicing impact, inside a (potentially) clinically important functional domain, where BP4 is met, and (ii) as an extension, to intronic variants located outside the conserved donor/acceptor motif positions (at or beyond +7/-21) where BP4 is met; a separate BP7_Strong (RNA) repurposing applies to well-established mRNA assays showing no aberrant transcript. None of these classes covers a frameshift/PTC variant, so BP7 is out of scope upstream of any predictor value, and the SpliceAI max delta score available for this variant (0.014) was not evaluated. No VCEP file pre-assigns a BP7 code for this variant.
Rule
ENIGMA BRCA2 Specifications v1.2, Table 1 (BP7 row) and Appendix J / Table 16: BP7 applies to a synonymous variant inside a (potentially) clinically important functional domain where BP4 is met, and (extension) to intronic variants at or beyond +7/-21 positions where BP4 is met; BP7_Strong (RNA) applies to mRNA assay evidence of no damaging effect in intronic/silent/missense-in-frame variants outside a clinically important domain.
Evidence considered
Scope check performed before any predictor score: the variant is a frameshift duplication with a premature termination codon (p.(Tyr2383SerfsTer11)) and is not synonymous; the PVS1 variant assessment records consequence_class 'frameshift'.
ENIGMA BRCA2 specification v1.2 (Table 1 BP7 row): 'Apply BP7 for Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.'
Appendix J, Table 16 (BP7 row): 'Following convention, this code is applied in addition to BP4 (no splicing prediction, Splice AI <= 0.1) to capture the low prior probability of pathogenicity of silent variants. Nucleotide conservation is not considered relevant. Apply BP7 for silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (BP4 met). Also apply BP7 for intronic variants located outside of conserved donor or acceptor motif positions (at or beyond positions +7/-21), if no predicted impact via splicing (BP4 met).'
Appendix E/Figure 9 context: the BP7_Strong (RNA) repurposing applies to intronic, silent and missense/in-frame variants outside a (potentially) clinically important functional domain on the basis of mRNA assay results showing no damaging effect; it likewise does not cover truncating frameshift variants.
The SpliceAI max delta score for this variant (0.014) was not used for BP7, since BP7 is defined for synonymous (and deep-intronic) variants and this variant is a frameshift.
No pre-assigned BP7 code was found in any declared VCEP file (searched Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, Specifications_Table4/9, SupplementaryTables and HUMU-40-1557-s001 for c.7141_7147dup, p.Tyr2383SerfsTer11 and p.Y2383Sfs*11).
Still missing
Searched the full text of Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx and PMID_22505045_Houdayer_2012_HumMutat.pdf for c.7141_7147dup, p.Tyr2383SerfsTer11 and p.Y2383Sfs*11: no variant-level or class-level BP7 entry exists for this variant. This is not an evidence gap affecting the verdict, because BP7 is out of scope by variant class (frameshift/truncating, not synonymous).
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
5 paper records listed. 3 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.
This paper does not report c.7141_7147dup or p.Y2383Sfs*11. It characterizes the mechanism by which BRCA2 truncating mutations lose function: two functional nuclear localization signals (NLS1, residues 3263-3269; NLS3, residues 3381-3385) reside within the final 156 residues of BRCA2, and GFP-tagged deletion constructs lacking this C-terminal region, like the endogenous cancer-associated 6174delT truncation, were cytoplasmically localized rather than nuclear by confocal microscopy and subcellular fractionation. Because the frameshift allele p.(Y2383Sfs*11) truncates the protein at codon 2393, upstream of these NLSs, the mechanism described predicts a nucleus-excluded, non-functional gene product. Gene-level mechanism evidence only: the paper contains no data specific to this variant.
Consequently, truncation mutant forms of BRCA2 are predicted to encode nucleus-excluded gene products, providing a simple explanation for why these mutants are nonfunctional: they do not translocate into the nucleus.
Location Introduction, final paragraph (also stated in Discussion, paragraph 1)
Context GFP-tagged full-length and deletion-mutant BRCA2 constructs transiently transfected into 293T cells, analyzed by confocal fluorescence microscopy and biochemical cytoplasmic/nuclear fractionation/Western blot; endogenous BRCA2 in MCF-7 cells and the endogenous 6174delT truncation in Capan-1 cells were also examined.
BRCA2 is required for homology-directed repair of chromosomal breaks.
This paper does not report the queried variant. It provides functional evidence that BRCA2 is required for efficient homology-directed repair (HDR) of chromosomal double-strand breaks: BRCA2-deficient human CAPAN-1 cells (6174delT, a frameshift truncating within BRC repeat 7) show a >100-fold reduction in homologous repair versus other human cell lines, and targeted deletion of Brca2 exon 27 (removing the C-terminal Rad51-interacting domain) reduced HDR 5- to 6-fold and gene targeting ~1.8-fold in mouse ES cells. The paper establishes that C-terminal truncation/frameshift mutations in BRCA2 impair HDR, but the specific allele c.7141_7147dup (p.Y2383Sfs*11) is not named or tested.
The magnitude of the defect in the human CAPAN-1 cells is .100-fold as compared with other human cell lines, whereas in the Brca2lex1/lex2 ES cells, HDR is reduced 5- to 6-fold relative to wild-type ES cells. Thus, the severity of the defect was significantly greater in cells that express a highly truncated BRCA2 protein than in cells in which only the most C-terminal Rad51-interacting domain is perturbed.
Location Discussion, paragraph 2
Context Functional HDR assay using the I-SceI endonuclease and an integrated DR-GFP gene-conversion reporter in human CAPAN-1 pancreatic adenocarcinoma cells (6174delT BRCA2) and murine Brca2lex1/lex2 embryonic stem cells (exon 27 C-terminal deletion); gene-targeting assay at the pim1 locus.
BRCA1 and BRCA2: different roles in a common pathway of genome protection.
This narrative review does not mention c.7141_7147dup or p.Y2383Sfs*11. It describes BRCA2's primary function as mediating homologous recombination by recruiting RAD51 to DNA double-strand breaks, and reports that loss-of-function/truncating BRCA2 mutants are defective in RAD51 recruitment and HR repair. It also notes that the C-terminal RAD51-binding region appears dispensable for HR in vivo, a general caveat about the extreme C-terminus rather than a statement about this allele, and provides no variant-specific functional, segregation, case or frequency data.
BRCA2-deficient cells are defective in recruiting RAD51 to sites of DSBs and in repairing DSBs by HR
Location BRCA2, HR and replication fidelity, first paragraph
Context Narrative review (no primary experimental data reported for this variant).
Other recorded publications
A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.
This paper does not report the queried variant. It describes a different heterozygous germline BRCA2 frameshift insertion in a single Italian family: 7525_7526insT (coding-sequence numbering; 7753insT in complete-mRNA NM_000059.3 numbering), producing p.Ser2509fs with a premature stop 29 codons downstream at position 2538. The frameshift truncates the protein by 881 amino acids (2537 aa instead of 3418 aa), removing part of the ssDNA-binding DBD, both C-terminal nuclear localization signals and the extreme C-terminal Rad51-binding motif. Gene/mechanism-level content only, for a different allele.
In this study, we have identified in a Italian healthy woman a pathological mutation in exon 15, the 7525_7526insT [in reference to coding sequence, NP_000050.2; 7753insT in reference to complete mRNA NM_000059.3], that causes a frame shift [p.Ser2509fs], resulting in a stop codon 29 amino acids downstream.
Results, paragraph 1 (variant also stated in the Abstract)
A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.
This global review of BRCA1/BRCA2 mutations does not name, table, or report the variant c.7141_7147dup (p.Y2383Sfs*11). It provides gene/mechanism-level context only: BRCA2 mutations are predominantly insertions or deletions, occur mostly in exons 10 and 11, typically cause frameshifts and premature stop codons producing truncated non-functional protein, and the C-terminal region carrying the DNA-binding domain, nuclear localization signals and Rad51-binding motif is critical for function.
In BRCA2 gene, most of mutations occur in exons 10 and 11 and usually include insertions or deletions which raise the missense alterations and premature stop codon ending in truncated and nonfunctional protein.
Section 3 (BRCA1 and BRCA2 Mutations), paragraph 2
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