Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
This variantScenario
BenignPathogenic
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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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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.
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BP1Strong
BP1 · strong
Met (Strong): silent substitution outside clinically important functional domains (aa 10-40, 2481-3186) with no predicted splice impact (SpliceAI max delta 0.011 ≤0.1).
BP4Supporting
BP4 · supporting
Met (Supporting): SpliceAI max delta 0.011, below the ≤0.1 no-splicing-impact threshold for silent variants.
BP6Supporting
BP6 · supporting
Met (Supporting): ENIGMA expert panel classified this exact variant as Likely benign.
BP7Supporting
BP7 · supporting
Met (Supporting): silent variant with no predicted splice impact; no mRNA assay data were available to elevate to Strong.
Recorded classification: Likely benign
Likely Benign under ENIGMA BRCA1/BRCA2 VCEP v1.2: BP1 (Strong) plus BP4, BP6, BP7 (Supporting) satisfy the 1 Strong + ≥1 Supporting benign rule, short of Benign (requires Very Strong or ≥2 Strong).
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
21 / 1,613,994 alleles
gnomAD v4.1: 21 / 1,613,994 alleles. Recorded AF 1.30112e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.38209e-05; MAF= 0.00438%, 11/251022 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000543715; MAF= 0.05437%, 10/18392 alleles, homozygotes = 0); grpmax FAF= 0.00029491.
ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 4 not met · 10 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Variant NM_000059.4:c.2133C>T / NP_000050.3:p.(Cys711=) is a synonymous substitution within the large BRCA2 coding exon 11 (c.1910-6841).
No loss-of-function consequence is predicted: not a null variant type, and SpliceAI shows no meaningful splice disruption (max delta 0.01), so PVS1 is not applicable.
No protein length change occurs (synonymous substitution), so PM4 is not applicable.
BP3 is explicitly marked Not Applicable for BRCA2 by the ENIGMA VCEP specification, and is mechanistically irrelevant to a single-nucleotide synonymous variant in any case.
Variant NM_000059.4:c.2133C>T is synonymous (NP_000050.3:p.(Cys711=)), not a missense or truncating change, so PS1, PM5, and PP2 pathways (which under this VCEP concern missense-comparator or PTC-comparator logic) are structurally not applicable to this variant.
PM1 and PP2 are both explicitly flagged 'Not Applicable' for BRCA2 in the ENIGMA v1.2 specification criteria list itself, independent of variant type.
PM5 under this VCEP is repurposed for PTC comparator logic only (PM5_PTC); the case's own pm5_candidates scaffold confirms non-eligibility for classic same-residue missense PM5 search.
BP1_Strong is met: residue 711 lies outside both VCEP-defined clinically important functional domains (PALB2 binding aa 10-40; DNA binding aa 2481-3186), and SpliceAI shows no predicted splice impact (0.01 vs 0.1 threshold), satisfying the explicit silent-substitution BP1_Strong pathway.
This group adjudicates only PS3 and BS3 for BRCA2 NM_000059.4:c.2133C>T, a synonymous variant (p.Cys711=), per the ENIGMA BRCA1/BRCA2 VCEP specification v1.2 (cspec), which is the governing framework for this gene/variant.
Neither criterion could be applied because no variant-specific calibrated functional assay result (protein, mRNA+protein, or RNA-only) for c.2133C>T was found in the VCEP's curated Table 9 dataset, the partial Dace & Findlay SGE interim report excerpt, or the case's reviewed literature.
Variant NM_000059.4:c.2133C>T, p.(Cys711=), is synonymous and not at the canonical +/-1,2 splice consensus positions.
SpliceAI predicts no significant splice impact (max delta = 0.011), well below the ENIGMA VCEP PP3 threshold (>=0.2) and satisfying the BP4/BP7 no-impact threshold (<=0.1).
PP3 not met (SpliceAI below the 0.2 pathogenic-impact threshold); no missense/BayesDel path applies since the variant is synonymous.
BP4 met at Supporting strength via the silent-variant SpliceAI <=0.1 pathway.
BP7 met at Supporting strength (BP4-met precondition satisfied); Strong (RNA) tier not applied due to absence of identified variant-specific mRNA/minigene functional splicing data in this bundle.
No criteria match.
Met · 4
BP1StrongMet (Strong): silent substitution outside clinically important functional domains (aa 10-40, 2481-3186) with no predicted splice impact (SpliceAI max delta 0.011 ≤0.1).
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Reasoning
The ENIGMA BRCA1/2 v1.2 BP1 rule explicitly permits silent substitutions: '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).' Clinically important functional domains for BRCA2 under this VCEP are defined as the PALB2 binding domain (aa 10-40) and the DNA binding domain (aa 2481-3186). Residue 711 (NP_000050.3:p.Cys711=) falls outside both defined domains. SpliceAI predicts no splice impact (max delta = 0.01, well below the 0.1 threshold). Both conditions of the BP1_Strong rule are met.
Rule
BP1_Strong
Evidence considered
cspec BP1 rule: '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). ... clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186.'
Variant residue is Cys711 (NP_000050.3:p.(Cys711=)), which falls outside both the PALB2 binding domain (aa 10-40) and the DNA binding domain (aa 2481-3186) defined by this VCEP as clinically important functional domains.
SpliceAI evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01)', satisfying the SpliceAI ≤0.1 threshold required for BP1_Strong.
BP4SupportingMet (Supporting): SpliceAI max delta 0.011, below the ≤0.1 no-splicing-impact threshold for silent variants.
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Reasoning
Per ENIGMA VCEP v1.2 (cspec), BP4 for a silent variant applies when SpliceAI <=0.1 (no predicted splicing impact), independent of functional domain location. SpliceAI max delta score for NM_000059.4:c.2133C>T is 0.011, well under 0.1. This synonymous variant qualifies for BP4 at the default (Supporting) strength.
Rule
ENIGMA BRCA1/BRCA2 VCEP v1.2, BP4 (silent-variant splicing path): SpliceAI <=0.1 satisfied by observed max delta 0.011.
Evidence considered
ENIGMA BRCA1/BRCA2 v1.2 specification (cspec), BP4 rule: 'Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI <=0.1).' The rule structure and Figure 1A apply the SpliceAI <=0.1 no-impact threshold to silent variants generally, regardless of domain location.
SpliceAI Lookup evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).' Scores: DS_AG=0.011, DS_AL=0.001, DS_DG=0.005, DS_DL=0.0, max_delta=0.011, satisfying the SpliceAI <=0.1 no-impact criterion for BP4.
BP6SupportingMet (Supporting): ENIGMA expert panel classified this exact variant as Likely benign.
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Reasoning
Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Likely benign.
Rule
BP6 is Supporting only for an exact-variant ClinVar expert-panel Benign or Likely benign assertion.
Evidence considered
ClinVar variation 185999 is NM_000059.4(BRCA2):c.2133C>T (p.Cys711=) and includes ENIGMA submission SCV000578995, classified Likely benign with review status 'reviewed by expert panel'.
BP7SupportingMet (Supporting): silent variant with no predicted splice impact; no mRNA assay data were available to elevate to Strong.
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Reasoning
ENIGMA VCEP v1.2 (cspec) applies BP7 at Supporting strength for a silent variant when BP4 is met (SpliceAI <=0.1, satisfied above at max delta 0.011) and no well-established mRNA functional assay data are available to elevate to BP7_Strong (RNA). No case-specific mRNA/minigene splicing assay results for this exact variant were found in the bundled evidence (evidence.json/vcep_materials.json/literature_pass.json), so the Strong (RNA-based) tier is not applicable; BP7 is applied at the default Supporting strength per the bioinformatic-prediction-only pathway.
Rule
ENIGMA BRCA1/BRCA2 VCEP v1.2, BP7 Supporting: silent variant with BP4 met (bioinformatic-only pathway; no mRNA functional assay data available to justify BP7_Strong).
Evidence considered
ENIGMA BRCA1/BRCA2 v1.2 specification (cspec), BP7 rule: 'Silent variant inside a (potentially) clinically important functional domain, IF BP4 met... Following convention, this code is applied in addition to BP4 (no splicing prediction, SpliceAI <=0.1) to capture the low prior probability of pathogenicity of silent variants.' BP7_Strong (RNA) requires well-established in vitro/in vivo mRNA transcript-profile functional data, which was not identified for this variant in the bundle.
SpliceAI Lookup evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).' max_delta=0.011, confirming the BP4-met precondition for BP7_Supporting.
Still missing
No variant-specific mRNA/minigene splicing assay data identified for c.2133C>T in the bundled evidence; if such functional data exist (e.g. in Houdayer et al. 2012 supplementary tables) they were not located for this specific variant and could support elevation to BP7_Strong (RNA) if reviewed.
PM2Not met: observed in gnomAD (11/251,022 alleles; grpmax FAF 0.00029), so not absent from population controls.
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Reasoning
PM2_Supporting requires absence from eligible gnomAD controls with adequate regional read depth. This variant is observed in gnomAD v2.1 (11/251022 alleles; grpmax FAF 0.00029491) and gnomAD v4.1 (21/1613994 alleles; grpmax FAF 0.00029482), so it is not absent from population controls.
Rule
ENIGMA BRCA1/2 v1.2 PM2_Supporting: absent from gnomAD v2.1 non-cancer exome-only and gnomAD v3.1 non-cancer controls, with regional average read depth >=25.
Evidence considered
ENIGMA BRCA1/2 v1.2 permits PM2 only at Supporting strength when a variant is absent from gnomAD v2.1 non-cancer exome-only and gnomAD v3.1 non-cancer controls and the region has average read depth of at least 25.
gnomAD v2.1 reports 11 variant alleles among 251022 alleles, including 10 East Asian alleles, with zero homozygotes.
gnomAD v4.1 independently reports 21 variant alleles among 1613994 alleles, including 20 East Asian alleles, with zero homozygotes.
Still missing
The provided bundle does not report the eligible non-cancer v3.1 result or regional average depth, but neither missing datum can restore PM2 while the variant is observed in gnomAD v2.1.
PP3Not met: SpliceAI max delta 0.011, far below the ≥0.2 threshold required for silent variants.
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Reasoning
NM_000059.4:c.2133C>T (p.(Cys711=)) is a synonymous variant not located at the canonical +/-1,2 splice consensus positions. Per ENIGMA ClinGen VCEP BRCA1/BRCA2 v1.2 specification (cspec), PP3 for silent variants requires predicted splicing impact with SpliceAI >=0.2 (irrespective of location in a clinically important functional domain). SpliceAI lookup for this variant returns a maximum delta score of 0.011 (DS_AG 0.011, DS_AL 0.001, DS_DG 0.005, DS_DL 0.0), far below the 0.2 threshold. No BayesDel/REVEL missense-path applies since this is a synonymous change, not a missense substitution. PP3 is therefore not met.
ENIGMA BRCA1/BRCA2 v1.2 specification (cspec), PP3 rule: '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 donor and acceptor 1,2 sites.'
SpliceAI Lookup evidence_sentence for this variant: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).' Scores: DS_AG=0.011, DS_AL=0.001, DS_DG=0.005, DS_DL=0.0, max_delta=0.011, well below the ENIGMA PP3 SpliceAI >=0.2 threshold.
PP5Not met: the ClinVar expert-panel assertion is Likely benign, not Pathogenic/Likely pathogenic, so it cannot support PP5.
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Reasoning
ClinVar contains an exact-variant expert-panel assertion, but it is Likely benign rather than Pathogenic/Likely pathogenic; thus it cannot support PP5. Ordinary laboratory submissions and aggregate labels were not used.
Rule
PP5 is Supporting only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion.
Evidence considered
The exact ClinVar record VCV000185999 includes an ENIGMA expert-panel submission (SCV000578995) classified Likely benign, reviewed by expert panel.
Still missing
An exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion would be required.
BA1Not met: gnomAD grpmax FAF 0.00029, below the BA1 threshold of >0.001.
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Reasoning
The observed gnomAD v2.1 grpmax FAF (0.00029491) and gnomAD v4.1 grpmax FAF (0.00029482) are both below the ENIGMA BA1 threshold of FAF >0.001 in an eligible non-founder population.
ENIGMA BRCA1/2 v1.2 specifies BA1 when FAF is >0.001 in gnomAD v2.1 non-cancer exome-only and/or gnomAD v3.1 non-cancer, non-founder populations.
gnomAD v2.1 reports 11/251022 alleles overall, East Asian AF 0.000543715, and grpmax FAF 0.00029491; no homozygotes were reported.
gnomAD v4.1 independently reports 21/1613994 alleles overall, East Asian AF 0.000445772, and grpmax FAF 0.00029482; no homozygotes were reported.
Still missing
The provided extracts do not document the ENIGMA-required non-cancer subset for either gnomAD release; this does not affect the conclusion that the reported FAFs are below the BA1 threshold.
PS3Not assessed: no variant-specific functional assay results were identified, so insufficient evidence was available.
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Reasoning
NM_000059.4:c.2133C>T (p.Cys711=) is a synonymous BRCA2 variant. The ENIGMA BRCA1/2 VCEP specification v1.2 (cspec) defines PS3 as applicable when well-established in vitro/in vivo functional studies (protein-only, mRNA+protein combined, or mRNA-only/RNA assay) show a damaging effect, with variant-specific code assignments curated in Specifications Table 9 (vcep_specifications_table9_v1_2_2024_11_18). This variant is not listed in the extracted Table 9 curated functional-assay entries, is not present in the Dace & Findlay interim saturation-genome-editing report rows reviewed (which cover a different exon 3 region, c.213-c.301), and no paper in the case's literature set reports a functional assay (minigene, mRNA, HDR, SGE, or other) for this specific variant. No variant-specific functional evidence supporting a damaging effect was identified.
Evidence considered
Searched ENIGMA Specifications Table 9 (vcep_specifications_table9_v1_2_2024_11_18) curated PS3/BS3 functional-assay variant list; c.2133C>T is not among the listed entries.
Searched Dace & Findlay Interim Report rows (partial excerpt in vcep_materials) for c.2133C>T; not present in the reviewed rows.
Reviewed literature_pass.json high/medium priority paper list; no paper flagged with theme=functional reports an assay result specific to c.2133C>T (the two theme=functional PMIDs, 25741868 and 26467025, are ACMG/AMP and Sherloc scoring-framework methodology papers, not variant-specific functional assay reports).
Still missing
No calibrated PS3 assay result for c.2133C>T found in ENIGMA Table 9 curated functional dataset
No mRNA/splicing functional assay (minigene or patient RNA) reported for this specific variant in the reviewed literature
Dace & Findlay SGE interim dataset excerpt available in the bundle does not cover this variant's position
PS4Not assessed: no exact-variant case-control study meeting the ENIGMA threshold (p≤0.05, OR≥4) was identified.
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Reasoning
No exact-variant, ethnicity- and country-matched case-control study reporting the ENIGMA PS4 threshold (p<=0.05, OR>=4, and lower confidence limit excluding 2.0) was identified.
Rule
ENIGMA BRCA2 v1.2 PS4: case-control p<=0.05, OR>=4, lower confidence interval excludes 2.0; use ethnicity- and country-matched controls and do not use proband counting.
Evidence considered
ENIGMA BRCA2 PS4 requires a case-control study with p<=0.05, OR>=4, and a lower confidence interval excluding 2.0; it does not permit proband counting.
The specifically reviewed exact-variant literature candidate PMID 22970155 did not mention BRCA2 c.2133C>T or p.Cys711= and therefore supplies no case count or case-control estimate for this variant.
Still missing
An exact-variant case-control comparison with effect estimate, confidence interval, and p-value is required.
PM3Not assessed: no Fanconi-anemia proband observation, second BRCA2 variant, or phase data were available.
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Reasoning
PM3 cannot be assessed. The BRCA2 ENIGMA specification restricts PM3 to probands with a phenotype consistent with BRCA1/2-related Fanconi anemia and a co-occurring variant in BRCA2, with points assigned from proband-level evidence. The bundle provides no affected-proband observation, Fanconi-anemia phenotype or chromosome-breakage result, second BRCA2 variant, pathogenic/likely pathogenic classification of a co-variant, or phase result for c.2133C>T.
Rule
ClinGen ENIGMA BRCA2 v1.2 PM3: apply only for a proband with BRCA1/2-related Fanconi anemia and co-occurring BRCA2 variant(s); assign Supporting, Moderate, or Strong only after Table 6 point scoring.
Evidence considered
The ClinGen ENIGMA BRCA2 v1.2 PM3 rule requires a phenotype consistent with BRCA1/2-related Fanconi anemia plus co-occurring variants in the same gene; PM3 strength is determined from the sum of Table 6 proband points.
The consolidated case-evidence bundle identifies the assessed allele as NM_000059.4:c.2133C>T, p.(Cys711=), but contains no individual-level Fanconi-anemia case, co-variant, inheritance, or phase evidence.
Still missing
Affected-proband data with a BRCA1/2-related Fanconi-anemia phenotype, including DEB/MMC/spontaneous chromosome-breakage testing or the specified clinical features.
Identification and VCEP-based classification of any co-occurring BRCA2 variant.
Parental/offspring testing or other validated phasing evidence establishing trans versus cis configuration.
Independent proband count and severity information needed to assign ENIGMA PM3 points.
PP1Not assessed: no family genotype and phenotype data or co-segregation likelihood ratio was available.
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Reasoning
No family-level genotype and phenotype data or quantitative co-segregation likelihood ratio is provided for NM_000059.4:c.2133C>T.
Rule
ENIGMA BRCA1/BRCA2 VCEP v1.2: apply PP1 only for quantitative co-segregation evidence meeting the specified LR thresholds.
Evidence considered
The ENIGMA BRCA1/BRCA2 VCEP framework requires quantitative co-segregation analysis for PP1, with thresholds of LR >=2.08 (Supporting), >=4.3 (Moderate), >=18.7 (Strong), and >=350 (Very Strong).
The consolidated case-evidence bundle contains no reported relatives, meioses, familial genotype results, phenotype concordance data, or variant-specific segregation LR.
Still missing
Obtain pedigree-level genotypes and disease status for affected and informative unaffected relatives, then calculate a quantitative co-segregation likelihood ratio.
PP4Not assessed: no calibrated multifactorial likelihood ratio toward pathogenicity (LR ≥2.08) was available.
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Reasoning
For BRCA2-related cancer predisposition, ENIGMA permits PP4 only from a clinically calibrated multifactorial likelihood ratio toward pathogenicity. No exact c.2133C>T clinical-history or combined multifactorial LR >=2.08 was available.
Rule
ENIGMA BRCA2 v1.2 PP4: use only a calibrated multifactorial LR toward pathogenicity; Supporting LR>=2.08, Moderate>=4.3, Strong>=18.7, Very Strong>=350.
Evidence considered
The BRCA2 clinical-history LR table was checked for c.2133C>T; it contains no exact matching row.
ENIGMA PP4 strength requires LR>=2.08 (Supporting), >=4.3 (Moderate), >=18.7 (Strong), or >=350 (Very Strong); breast cancer alone is not phenotype-specific enough for PP4.
Still missing
An exact-variant clinical-history LR or a sourced combined multifactorial LR >=2.08 is required.
BS1Not assessed: FAF 0.00029 exceeds the BS1_Strong threshold of >0.0001, but the required gnomAD non-cancer subset was not documented.
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Reasoning
The reported grpmax FAFs (0.00029491 in gnomAD v2.1 and 0.00029482 in gnomAD v4.1) exceed the ENIGMA BS1_Strong threshold of >0.0001. However, ENIGMA requires that threshold to be evaluated in the gnomAD v2.1 non-cancer exome-only subset and/or gnomAD v3.1 non-cancer data. The supplied data identify v2.1 exome and v4.1 records but do not document the required non-cancer subset, and v4.1 is not one of the specified releases. A strong BS1 assertion therefore cannot be made from this bundle alone.
Rule
ENIGMA BRCA1/2 v1.2 BS1: Strong if FAF >0.0001; Supporting if FAF >0.00002 to <=0.0001, in gnomAD v2.1 non-cancer exome-only and/or gnomAD v3.1 non-cancer, non-founder population(s).
Evidence considered
ENIGMA BRCA1/2 v1.2 defines BS1_Strong as FAF >0.0001 and BS1_Supporting as FAF >0.00002 to <=0.0001, specifically in gnomAD v2.1 non-cancer exome-only and/or gnomAD v3.1 non-cancer, non-founder populations.
gnomAD v2.1 reports a grpmax FAF of 0.00029491 and highest observed East Asian AF of 0.000543715 (10/18392 alleles; zero homozygotes).
gnomAD v4.1 reports a similar grpmax FAF of 0.00029482 and East Asian AF of 0.000445772 (20/44866 alleles; zero homozygotes), corroborating an ancestry-enriched signal but not substituting for the specified non-cancer v2.1/v3.1 evidence.
Still missing
Verify the variant's FAF in the gnomAD v2.1 non-cancer exome-only subset and/or gnomAD v3.1 non-cancer data.
Confirm that the East Asian signal is in an ENIGMA-eligible non-founder population after the required subset filter.
BS2Not assessed: no observations in individuals without Fanconi anemia were available; absence of homozygotes alone is insufficient.
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Reasoning
No qualifying observations in individuals without Fanconi anemia phenotype are provided. The absence of homozygotes in gnomAD does not satisfy the ENIGMA point-based BS2 requirement and cannot be converted into BS2 evidence.
Rule
ENIGMA BRCA1/2 v1.2 BS2: absence of recessive-disease (Fanconi anemia) features with Table 8 point assignment; Supporting = 1 point, Moderate = 2 points, Strong = at least 4 points.
Evidence considered
ENIGMA BRCA1/2 v1.2 applies BS2 only in the absence of Fanconi anemia features and assigns Supporting, Moderate, and Strong at 1, 2, and at least 4 qualifying points, respectively.
gnomAD v2.1 and v4.1 each report zero homozygotes; these aggregate population counts lack phenotype information and are not qualifying BS2 observations.
Still missing
Provide ENIGMA Table 8-qualifying observations of the variant in individuals documented to lack Fanconi anemia features, with sufficient point total for a BS2 strength assignment.
BS3Not assessed: no variant-specific functional assay result was identified; the SpliceAI prediction is bioinformatic only and cannot substitute.
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Reasoning
No calibrated functional assay result for NM_000059.4:c.2133C>T (p.Cys711=) was identified in the ENIGMA BRCA1/2 VCEP curated functional-assay dataset (Specifications Table 9) or in the reviewed literature/vcep materials. BS3 per the cspec requires well-established in vitro/in vivo (protein-only, mRNA+protein combined, or RNA-only) functional studies showing no damaging effect; without a variant-specific published/calibrated assay result, BS3 cannot be assessed. SpliceAI shows no significant splice-impact prediction for this variant (max delta score = 0.01, per prefetch/spliceai data), but this is a bioinformatic splice prediction relevant to PP3/BP4/BP7, not a functional assay result, and is therefore insufficient on its own to support BS3.
Evidence considered
Searched ENIGMA Specifications Table 9 (vcep_specifications_table9_v1_2_2024_11_18) curated PS3/BS3 functional-assay variant list; c.2133C>T is not among the listed entries.
Searched Dace & Findlay Interim Report rows (partial excerpt in vcep_materials) for c.2133C>T; not present in the reviewed rows.
Noted SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01) per prefetch spliceai evidence_sentence, but this is bioinformatic-only evidence and not a substitute for a functional assay under the ENIGMA BS3 rule.
Still missing
No calibrated BS3 assay result for c.2133C>T found in ENIGMA Table 9 curated functional dataset
No mRNA/splicing functional assay (minigene or patient RNA) reported for this specific variant in the reviewed literature
SpliceAI negative prediction is bioinformatic only and does not substitute for a functional assay under the VCEP BS3 rule
BS4Not assessed: no quantitative evidence of non-segregation in affected family members was available.
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Reasoning
No quantitative evidence of non-segregation in affected family members is provided for NM_000059.4:c.2133C>T.
Rule
ENIGMA BRCA1/BRCA2 VCEP v1.2: apply BS4 only for quantitative lack-of-segregation evidence meeting the specified LR thresholds.
Evidence considered
The ENIGMA BRCA1/BRCA2 VCEP framework requires quantitative lack-of-segregation evidence for BS4, with LR <=0.48 (Supporting), <=0.23 (Moderate), <=0.05 (Strong), or <=0.00285 (Very Strong).
The consolidated case-evidence bundle contains no reported affected relatives lacking the variant and no variant-specific non-segregation LR.
Still missing
Obtain pedigree-level genotypes and disease status for affected relatives and calculate a quantitative non-segregation likelihood ratio.
BP5Not assessed: no calibrated multifactorial likelihood ratio against pathogenicity (LR ≤0.48) was available.
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Reasoning
ENIGMA BRCA2 BP5 requires a calibrated multifactorial LR against pathogenicity. No exact c.2133C>T clinical-history or combined multifactorial LR <=0.48 was available. The ClinVar expert-panel classification was not used as a substitute for this criterion.
Rule
ENIGMA BRCA2 v1.2 BP5: use only a calibrated multifactorial LR against pathogenicity; Supporting LR<=0.48, Moderate<=0.23, Strong<=0.05, Very Strong<=0.00285.
Evidence considered
The BRCA2 clinical-history LR table was checked for c.2133C>T; it contains no exact matching row.
ENIGMA BP5 strength requires LR<=0.48 (Supporting), <=0.23 (Moderate), <=0.05 (Strong), or <=0.00285 (Very Strong); co-observation in different breast-ovarian cancer risk genes is not eligible.
Still missing
An exact-variant clinical-history LR or a sourced combined multifactorial LR <=0.48 is required.
Not applicable · 10· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: synonymous change with no predicted splice impact (SpliceAI max delta 0.01), so no null-variant pathway applies.
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Reasoning
NM_000059.4:c.2133C>T is a synonymous substitution (NP_000050.3:p.(Cys711=)) located within the large coding exon spanning c.1910-6841 (BRCA2 exon 11). It is not a null variant type (not nonsense, frameshift, canonical +/-1,2 splice site, initiation codon, or single/multi-exon deletion) as required by the ENIGMA BRCA2 PVS1 rule and by generic ACMG PVS1 criteria. SpliceAI predicts no significant splice impact (max delta score = 0.01, well below the ENIGMA/PP3-BP4 SpliceAI threshold of 0.2/0.1), so there is no computational signal of cryptic splice-site creation, exon skipping, or NMD-triggering transcript disruption that would justify applying PVS1 via the RNA/mRNA pathway. PVS1 is therefore not applicable for this variant.
Rule
ENIGMA BRCA2 CSPEC v1.2: PVS1 applies only to null variant types or mRNA-assay-confirmed damaging splice effects; this synonymous variant is neither.
Evidence considered
ENIGMA BRCA2 CSPEC v1.2 (cspec source) defines PVS1 applicability to null variants (nonsense, frameshift, splice site donor/acceptor +/-1,2, initiation codon, single/multi-exon deletion) or well-established mRNA-assay-supported damaging splice effects (PVS1 RNA pathway); this synonymous SNV meets neither category.
SpliceAI Lookup evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01)' (DS_AG=0.011, DS_AL=0.001), well below the ENIGMA BP4/PP3 SpliceAI thresholds (>=0.2 pathogenic-predictive, <=0.1 benign-predictive), supporting no splice-mediated LOF mechanism.
PS1N/ANot applicable: no amino acid change occurs and SpliceAI max delta 0.01 predicts no splicing impact, so no PS1 pathway applies.
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Reasoning
NM_000059.4:c.2133C>T is a synonymous change, NP_000050.3:p.(Cys711=) — no amino acid substitution occurs. The ENIGMA BRCA1/2 v1.2 PS1 rule requires either (a) a predicted missense substitution matching the amino-acid change of a previously classified pathogenic/likely pathogenic variant acting via protein change, or (b) an exonic/intronic variant with the same predicted splicing impact as a previously classified (likely) pathogenic variant. This variant produces neither a missense change nor a predicted splicing impact (SpliceAI max delta = 0.01, well below the 0.1 threshold used throughout this VCEP spec), so no PS1 pathway is met.
Evidence considered
cspec Specifications v1.2 PS1 rule requires either a matching missense substitution to a known (likely) pathogenic variant acting via protein change, or matching splicing impact to a known (likely) pathogenic variant.
Variant normalizes to NP_000050.3:p.(Cys711=), a synonymous change with no amino acid substitution, so the missense-comparator PS1 pathway is structurally inapplicable.
SpliceAI evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01)', below the 0.1 threshold used for the splicing PS1 pathway.
PM1VCEPNot applicable: this VCEP marks PM1 Not Applicable for BRCA2; domain evidence is handled through other criteria.
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Reasoning
The ENIGMA BRCA1/2 v1.2 specification explicitly marks PM1 as Not Applicable for BRCA2 in this framework (label PM1, applicability: Not Applicable in cspec criteria list). This VCEP replaces the generic mutational-hotspot/domain PM1 concept with domain-aware handling folded into PP3/BP4/BP7/BP1 (clinically important functional domains: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186). No separate PM1 code is available to apply.
Evidence considered
cspec case_summary compact_evidence criteria list explicitly lists {"label": "PM1", "applicability": "Not Applicable"} for this ENIGMA BRCA1/BRCA2 v1.2 specification.
PM4VCEPNot applicable: synonymous change does not alter protein length or the stop codon.
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Reasoning
PM4 addresses protein length changes from in-frame indels or stop-loss variants. NM_000059.4:c.2133C>T is a synonymous substitution (p.(Cys711=)) that does not alter the length of the BRCA2 protein or remove/extend the stop codon. There is no protein length change to evaluate, so PM4 is not applicable.
VCEP rule
Generic ACMG PM4: applies only to in-frame indels or stop-loss variants producing a protein length change; not applicable to synonymous substitutions.
Evidence considered
Normalized protein consequence NP_000050.3:p.(Cys711=) confirms a synonymous change with no alteration to protein length, ruling out any in-frame insertion/deletion or stop-loss mechanism relevant to PM4.
PM5N/ANot applicable: reserved for PTC-comparator logic; this synonymous change is not a protein-termination or missense variant.
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Reasoning
Under this VCEP, PM5 is repurposed exclusively for protein-termination-codon (PTC) comparator logic (PM5_PTC: a different proven pathogenic PTC variant seen previously in the same exon, per Specifications Table 4 exon-level applicability), not for classic same-residue missense comparators. This variant is synonymous (p.Cys711=), not a PTC/missense variant, so the PM5_PTC pathway does not apply. The case's own pm5_candidates scaffold confirms pm5_mode is 'ptc_gene_specific' with eligible_for_classic_pm5_search=false and recommendation level 'not_applicable', and reports zero same-residue candidates collected.
Evidence considered
cspec Specifications v1.2 PM5 rule: '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.' This is a PTC-only repurposing of PM5, not applicable to synonymous variants.
No classic same-residue missense comparator search was performed since this VCEP repurposes PM5 for PTC logic only, and this variant is neither a missense nor a PTC/truncating variant.
PP2VCEPNot applicable: marked Not Applicable for BRCA2 in this VCEP; the variant is also synonymous, not missense.
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Reasoning
The ENIGMA BRCA1/2 v1.2 specification explicitly marks PP2 as Not Applicable for BRCA2 (label PP2, applicability: Not Applicable in cspec criteria list). PP2 (missense in a gene with low benign missense rate and where missense is a common disease mechanism) is not part of this VCEP's applied code set, and in any case this variant is synonymous, not missense.
Evidence considered
cspec case_summary compact_evidence criteria list explicitly lists {"label": "PP2", "applicability": "Not Applicable"} for this ENIGMA BRCA1/BRCA2 v1.2 specification.
Variant is synonymous (p.Cys711=), not a missense change, so PP2's underlying missense-mechanism logic would not apply regardless.
BP2VCEPNot applicable: designated Not Applicable for BRCA2 in the ENIGMA v1.2 specification.
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Reasoning
BP2 is not applicable under the governing ClinGen ENIGMA BRCA2 v1.2 specification. The specification states that BP2 is applied only in the context of BS2 and marks all BP2 strengths not applicable; therefore generic ACMG/AMP BP2 cis/trans logic is not substituted.
VCEP rule
ClinGen ENIGMA BRCA2 v1.2: BP2 not applicable; do not replace the gene-specific restriction with generic ACMG/AMP BP2.
Evidence considered
The ClinGen ENIGMA BRCA2 v1.2 criterion table lists BP2 as not applicable, with the instruction: 'Applied only in the context of BS2.'
BP3VCEPNot applicable: designated Not Applicable for BRCA2; also irrelevant to a single-nucleotide synonymous substitution.
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Reasoning
The governing ENIGMA BRCA2 CSPEC v1.2 explicitly designates BP3 as Not Applicable for BRCA2. Independently, BP3 (in-frame indel in a repetitive region without known function) is mechanistically irrelevant here since this is a single-nucleotide synonymous substitution, not an in-frame insertion/deletion in a repeat region. BP3 is therefore not applicable.
VCEP rule
ENIGMA BRCA2 CSPEC v1.2: BP3 = Not Applicable for BRCA2.
Evidence considered
ENIGMA BRCA2 CSPEC v1.2 (case_summary cspec.criteria) lists BP3 with applicability: 'Not Applicable' for BRCA2, overriding generic ACMG applicability regardless of variant type.
Variant is a synonymous single-nucleotide substitution, not an in-frame insertion/deletion, so the underlying BP3 mechanism (repetitive region indel with no known function) does not apply irrespective of the VCEP N/A designation.
AF 1.3e-05 · 21 / 1,613,994 alleles · 0 hom · FAF 0.00029
East Asian20 / 44,866
0.00045
South Asian1 / 91,082
1.1e-05
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 4.4e-05 · 11 / 251,022 alleles · 0 hom · FAF 0.00029
East Asian10 / 18,392
0.00054
South Asian1 / 30,616
3.3e-05
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.30112e-05; MAF= 0.00130%, 21/1613994 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000445772; MAF= 0.04458%, 20/44866 alleles, homozygotes = 0); grpmax FAF= 0.00029482.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.38209e-05; MAF= 0.00438%, 11/251022 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000543715; MAF= 0.05437%, 10/18392 alleles, homozygotes = 0); grpmax FAF= 0.00029491.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -223 bp
0.001
SpliceAI acceptor gainat +7 bp
0.011
SpliceAI donor lossat -330 bp
0.000
SpliceAI donor gainat +265 bp
0.005
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.044
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
BP4SupportingMet (Supporting): SpliceAI max delta 0.011, below the ≤0.1 no-splicing-impact threshold for silent variants.
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Reasoning
Per ENIGMA VCEP v1.2 (cspec), BP4 for a silent variant applies when SpliceAI <=0.1 (no predicted splicing impact), independent of functional domain location. SpliceAI max delta score for NM_000059.4:c.2133C>T is 0.011, well under 0.1. This synonymous variant qualifies for BP4 at the default (Supporting) strength.
Rule
ENIGMA BRCA1/BRCA2 VCEP v1.2, BP4 (silent-variant splicing path): SpliceAI <=0.1 satisfied by observed max delta 0.011.
Evidence considered
ENIGMA BRCA1/BRCA2 v1.2 specification (cspec), BP4 rule: 'Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI <=0.1).' The rule structure and Figure 1A apply the SpliceAI <=0.1 no-impact threshold to silent variants generally, regardless of domain location.
SpliceAI Lookup evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).' Scores: DS_AG=0.011, DS_AL=0.001, DS_DG=0.005, DS_DL=0.0, max_delta=0.011, satisfying the SpliceAI <=0.1 no-impact criterion for BP4.
BP7SupportingMet (Supporting): silent variant with no predicted splice impact; no mRNA assay data were available to elevate to Strong.
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Reasoning
ENIGMA VCEP v1.2 (cspec) applies BP7 at Supporting strength for a silent variant when BP4 is met (SpliceAI <=0.1, satisfied above at max delta 0.011) and no well-established mRNA functional assay data are available to elevate to BP7_Strong (RNA). No case-specific mRNA/minigene splicing assay results for this exact variant were found in the bundled evidence (evidence.json/vcep_materials.json/literature_pass.json), so the Strong (RNA-based) tier is not applicable; BP7 is applied at the default Supporting strength per the bioinformatic-prediction-only pathway.
Rule
ENIGMA BRCA1/BRCA2 VCEP v1.2, BP7 Supporting: silent variant with BP4 met (bioinformatic-only pathway; no mRNA functional assay data available to justify BP7_Strong).
Evidence considered
ENIGMA BRCA1/BRCA2 v1.2 specification (cspec), BP7 rule: 'Silent variant inside a (potentially) clinically important functional domain, IF BP4 met... Following convention, this code is applied in addition to BP4 (no splicing prediction, SpliceAI <=0.1) to capture the low prior probability of pathogenicity of silent variants.' BP7_Strong (RNA) requires well-established in vitro/in vivo mRNA transcript-profile functional data, which was not identified for this variant in the bundle.
SpliceAI Lookup evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).' max_delta=0.011, confirming the BP4-met precondition for BP7_Supporting.
Still missing
No variant-specific mRNA/minigene splicing assay data identified for c.2133C>T in the bundled evidence; if such functional data exist (e.g. in Houdayer et al. 2012 supplementary tables) they were not located for this specific variant and could support elevation to BP7_Strong (RNA) if reviewed.
PP3Not met: SpliceAI max delta 0.011, far below the ≥0.2 threshold required for silent variants.
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Reasoning
NM_000059.4:c.2133C>T (p.(Cys711=)) is a synonymous variant not located at the canonical +/-1,2 splice consensus positions. Per ENIGMA ClinGen VCEP BRCA1/BRCA2 v1.2 specification (cspec), PP3 for silent variants requires predicted splicing impact with SpliceAI >=0.2 (irrespective of location in a clinically important functional domain). SpliceAI lookup for this variant returns a maximum delta score of 0.011 (DS_AG 0.011, DS_AL 0.001, DS_DG 0.005, DS_DL 0.0), far below the 0.2 threshold. No BayesDel/REVEL missense-path applies since this is a synonymous change, not a missense substitution. PP3 is therefore not met.
ENIGMA BRCA1/BRCA2 v1.2 specification (cspec), PP3 rule: '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 donor and acceptor 1,2 sites.'
SpliceAI Lookup evidence_sentence for this variant: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).' Scores: DS_AG=0.011, DS_AL=0.001, DS_DG=0.005, DS_DL=0.0, max_delta=0.011, well below the ENIGMA PP3 SpliceAI >=0.2 threshold.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.
Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.
Risk assessment and genetic counseling for hereditary breast and ovarian cancer syndromes-Practice resource of the National Society of Genetic Counselors.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.30112e-05; MAF= 0.00130%, 21/1613994 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000445772; MAF= 0.04458%, 20/44866 alleles, homozygotes = 0); grpmax FAF= 0.00029482.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.38209e-05; MAF= 0.00438%, 11/251022 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000543715; MAF= 0.05437%, 10/18392 alleles, homozygotes = 0); grpmax FAF= 0.00029491.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign (1 clinical laboratory) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 185999)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 7.1.0.
The current version is 11.0.07.
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