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BRCA2c.8275delPathogenic
Print report
Variant interpretation report

BRCA2 c.8275del, p.(Val2759TrpfsTer18)

NM_000059.4:c.8275del NP_000050.3:p.(Val2759TrpfsTer18) Frameshift · exon 18 View identifiers
Classification
Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

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.

NCBI Gene ↗ OncoKB ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. 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.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

Met, very strong: the exon 18 frameshift c.8275del yields p.Val2759TrpfsTer18, and ENIGMA Table 4 assigns full PVS1 to BRCA2 exon 18 PTC variants.

PM5Strong
PM5 · strong

Met, strong: ENIGMA Table 4 assigns PM5 (PTC) strong to BRCA2 exon 18, where c.8275del produces a premature stop at p.2776.

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.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.095 maximum delta

Recorded SpliceAI maximum delta score: 0.095. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 2 not met · 9 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PVS1 is met at very strong strength under the ENIGMA BRCA2 exon 18 PTC rule for this transcript-relevant frameshift.

PM4 and BP3 are not applicable because the VCEP explicitly excludes both criteria and the variant is a premature-termination frameshift rather than an in-frame length change.

All three requested criteria are upstream not_applicable because the variant is a frameshift, not a missense, in-frame, splice-region/intronic, or synonymous variant within the criteria scopes.

The ENIGMA BRCA2 v1.2 VCEP specification governs and takes precedence over generic computational thresholds.

Met · 2

PVS1 Very strongMet, very strong: the exon 18 frameshift c.8275del yields p.Val2759TrpfsTer18, and ENIGMA Table 4 assigns full PVS1 to BRCA2 exon 18 PTC variants. Details ▾Hide ▴
Reasoning

NM_000059.4:c.8275del is a frameshift on the governing BRCA2 transcript, producing NP_000050.3:p.(Val2759TrpfsTer18) / p.(V2759Wfs*18). The normalized transcript exon map places c.8275 within BRCA2 exon 18 (c.7977-c.8331), and the predicted premature termination is within the internal coding region rather than the terminal exon, supporting loss of the transcript/protein through the established BRCA2 loss-of-function mechanism. ENIGMA BRCA1/2 V1.2 Table 1 directs application of the PVS1 flowchart and Table 4 assigns PVS1 to BRCA2 exon 18 PTC variants; no VCEP downgrade rule for exon 18 PTC/frameshift variants applies. Therefore PVS1 is met at full, very strong strength. Exact searches for c.8275del, p.Val2759TrpfsTer18, and p.V2759Wfs*18 found no variant-specific row in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, Specifications_Table4_V1.2_2024-11-18.xlsx, or PMID_22505045_Houdayer_2012_HumMutat.pdf; the governing exon-level Table 4 rule remains applicable.

Rule
ENIGMA BRCA1/2 V1.2 PVS1 flowchart and Specifications Table 4: BRCA2 exon 18 PTC/frameshift variants receive PVS1; full-strength PVS1 is reported as very strong.
Evidence considered
  • The normalized case annotation is NM_000059.4:c.8275del, NP_000050.3:p.(Val2759TrpfsTer18), with frameshift consequence.
  • The transcript exon map places c.8275 in BRCA2 exon 18, whose coding interval is c.7977-c.8331.
  • ENIGMA V1.2 Table 1 requires PVS1 application through the BRCA2-specific PVS1 flowchart; Table 4 lists BRCA2 exon 18 PTC as PVS1 and does not mark exon 18 as PVS1_N/A.
  • The ENIGMA framework identifies germline BRCA2 loss of function as an established disease mechanism and provides no exon 18 downgrade for this internal frameshift PTC.
  • The predicted protein change terminates after 18 altered amino acids from Val2759 and is not an in-frame or stop-loss consequence.
Still missing
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry was found in Specifications_V1.2_2024-11-18.docx; the exon-level rule was used.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry was found in Appendices_V1.2_2024-11-18.docx; the exon-level rule was used.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx; the BRCA2 exon 18 PTC row was used.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf; this splice-focused paper provides no variant-specific consequence evidence.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18pvs1_gene_context
PM5 StrongMet, strong: ENIGMA Table 4 assigns PM5 (PTC) strong to BRCA2 exon 18, where c.8275del produces a premature stop at p.2776. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification repurposes PM5 as PM5 (PTC) for germline nonsense and frameshift variants that meet PVS1, with strength determined by the exon containing the nucleotide change. The normalized variant NM_000059.4:c.8275del is in BRCA2 exon 18 and produces p.(Val2759TrpfsTer18), with the predicted termination at p.2776; Table 4 assigns PM5 (PTC) applicability to exon 18, and the exon 18 row has the strong PTC weighting. The rule is applicable despite the absence of an exact variant row because the governing pre-assigned exon-level rule controls.

Rule
For BRCA2 germline PVS1-eligible frameshift or nonsense variants, apply PM5 (PTC) using the pre-assigned strength for the exon containing the nucleotide change; exon 18 is strong.
Evidence considered
  • ENIGMA Appendix D states that PM5 (PTC) is applied to germline nonsense and frameshift variants meeting PVS1, with the weight determined by the exon containing the nucleotide change.
  • The normalized transcript consequence is NM_000059.4:c.8275del, p.(Val2759TrpfsTer18), with position_first 2758, position_last_predicted 2776, and exon 18 coordinates c.8176-c.8530.
  • ENIGMA Specifications Table 4 lists BRCA2 exon 18 as PTC-applicable and assigns the exon-level PM5 (PTC) entry the strong weighting.
Still missing
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt; the applicable exon-level E18 PM5 (PTC) rule is present.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18

Not met · 2 · evaluated, threshold not reached

BA1 Not met: the variant was absent from the specified gnomAD datasets, so no filter allele frequency exceeded the ENIGMA BA1 threshold of 0.001. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 VCEP specification assigns BA1 when maximum filter allele frequency exceeds 0.001 (0.1%) in a non-founder gnomAD population, using gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, with read depth >=20 and exclusion of failed QC data. The case evidence reports this deletion as absent from gnomAD v2.1, gnomAD v2.1 non-cancer, gnomAD v4.1, and gnomAD v3.1 non-cancer; therefore no observed allele frequency can exceed the BA1 threshold. No variant-specific row for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx.

Rule
ENIGMA BA1: maximum filter allele frequency >0.001 in a qualifying non-founder gnomAD population; read depth >=20; exclude failed QC data and established pathogenic founder variants.
Evidence considered
  • ENIGMA BRCA2 v1.2 specifies BA1 for maximum filter allele frequency >0.001 in a non-founder population, assessed separately in gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with read depth >=20 and QC exclusions.
  • The case evidence reports NM_000059.4:c.8275del (p.Val2759TrpfsTer18; p.V2759Wfs*18) absent from gnomAD v2.1, gnomAD v2.1 non-cancer, gnomAD v4.1, and gnomAD v3.1 non-cancer.
  • The governing VCEP files were searched under all three supplied variant notations; no variant-specific population entry was found.
Still missing
  • No variant-specific entry was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific entry was found in Appendices_V1.2_2024-11-18.docx.
  • No variant-specific entry was found in HUMU-40-1557-s001.xlsx.
  • The case evidence does not provide a local read-depth value or explicit QC field for this deletion.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001
BS1 Not met: the variant was absent from the specified gnomAD datasets, so no filter allele frequency exceeded the ENIGMA BS1 threshold of 0.0001. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 VCEP specification assigns BS1 when maximum filter allele frequency is >0.0001 (0.01%) and assigns BS1_Supporting when it is >0.00002 and <=0.0001, in a non-founder gnomAD population using non-cancer exomes/genomes, with read depth >=20 and QC exclusions. The case evidence reports the deletion as absent from gnomAD v2.1, gnomAD v2.1 non-cancer, gnomAD v4.1, and gnomAD v3.1 non-cancer; thus no observed frequency reaches either BS1 threshold. No variant-specific row for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx.

Rule
ENIGMA BS1: maximum filter allele frequency >0.0001 for BS1, or >0.00002 to <=0.0001 for BS1_Supporting, in a qualifying non-founder gnomAD population; read depth >=20 and QC exclusions apply.
Evidence considered
  • ENIGMA BRCA2 v1.2 specifies BS1 above 0.0001 and BS1_Supporting above 0.00002 through 0.0001, based on maximum filter allele frequency in qualifying non-founder gnomAD populations, with read depth >=20 and QC exclusions.
  • The case evidence reports NM_000059.4:c.8275del (p.Val2759TrpfsTer18; p.V2759Wfs*18) absent from gnomAD v2.1, gnomAD v2.1 non-cancer, gnomAD v4.1, and gnomAD v3.1 non-cancer.
  • The governing VCEP files were searched under all three supplied variant notations; no variant-specific population entry was found.
Still missing
  • No variant-specific entry was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific entry was found in Appendices_V1.2_2024-11-18.docx.
  • No variant-specific entry was found in HUMU-40-1557-s001.xlsx.
  • The case evidence does not provide a local read-depth value or explicit QC field for this deletion.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001

Not assessed · 9 · no assessment recorded

PS3 Not assessed: no governing VCEP Table 9 assignment or validated assay result reports BRCA2 c.8275del or p.(Val2759TrpfsTer18). Details ▾Hide ▴
Reasoning

Not assessed. The governing ENIGMA BRCA1/2 VCEP specification v1.2 applies PS3 to well-established functional assays measuring protein function alone or mRNA plus protein, with calibrated variant-specific recommendations in Table 9; mRNA-only damaging assays are assigned under the alternative PVS1 (RNA) framework. The exact variant NM_000059.4:c.8275del, p.(Val2759TrpfsTer18), and p.(V2759Wfs*18) was not found in Specifications_Table9_V1.2_2024-11-18.xlsx, which declares PS3/BS3 and contains calibrated assay assignments, nor in the other governing functional evidence files searched: Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, and HUMU-40-1557-s001.xlsx. The case-linked functional papers describe BRCA2 biology or different truncating variants, but none reports this exact variant in a validated assay. Therefore there is no exact-variant calibrated protein or combined mRNA/protein result sufficient to assign PS3.

Rule
ENIGMA PS3: well-established in vitro or in vivo functional studies supportive of a damaging effect, using protein-only or combined mRNA/protein assays; use the calibrated Table 9 recommendation when available.
Evidence considered
  • ENIGMA VCEP v1.2 specifies PS3 for well-established functional studies measuring protein function alone or mRNA and protein together; mRNA-only damaging results use the alternative PVS1 (RNA) code.
  • Specifications_Table9_V1.2_2024-11-18.xlsx was searched under all three supplied variant notations and contained no exact-variant PS3 assignment.
  • Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, and HUMU-40-1557-s001.xlsx were each searched under c.8275del, p.Val2759TrpfsTer18, and p.V2759Wfs*18; no exact-variant functional entry was found.
  • PMID:11239455 reports impaired homologous recombination in BRCA2-mutant cell lines carrying other BRCA2 alterations, not c.8275del; its result cannot be assigned as exact-variant PS3.
  • PMID:10570174 reports localization of other BRCA2 truncation constructs, including 6174delT, not c.8275del; its result cannot be assigned as exact-variant PS3.
  • PMID:20878484 reports a different BRCA2 exon 15 insertion, 7525_7526insT, not c.8275del; its result cannot be assigned as exact-variant PS3.
  • PMID:22193408 and PMID:24312913 provide general BRCA2 functional context without an exact-variant assay result.
Still missing
  • No exact variant entry found in Specifications_Table9_V1.2_2024-11-18.xlsx after searching c.8275del, p.Val2759TrpfsTer18, and p.V2759Wfs*18.
  • No exact variant entry found in Specifications_V1.2_2024-11-18.docx after searching c.8275del, p.Val2759TrpfsTer18, and p.V2759Wfs*18.
  • No exact variant entry found in Appendices_V1.2_2024-11-18.docx after searching c.8275del, p.Val2759TrpfsTer18, and p.V2759Wfs*18.
  • No exact variant entry found in HUMU-40-1557-s001.xlsx after searching c.8275del, p.Val2759TrpfsTer18, and p.V2759Wfs*18.
  • No validated exact-variant protein or combined mRNA/protein functional assay result was identified in the case-linked literature.
  • The available exact-variant evidence is limited to predicted truncation/protein consequence and does not provide a PS3-calibrated functional measurement.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001vcep_specifications_table9_v1_2_2024_11_18PMID:10570174 ↗PMID:11239455 ↗PMID:20878484 ↗PMID:22193408 ↗PMID:24312913 ↗
PS4 Not assessed: no variant-specific case-control OR, p-value, or confidence interval was available to evaluate the ENIGMA OR ≥4 and p-value ≤0.05 requirements. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 specification requires case-control evidence with p-value ≤0.05, OR ≥4, and a lower confidence interval excluding 2.0. The case bundle contains no variant-specific case-control counts, odds ratio, confidence interval, or p-value for NM_000059.4:c.8275del (p.Val2759TrpfsTer18; p.V2759Wfs*18). Searches of SupplementaryTables_V1.2.xlsx and HUMU-40-1557-s001.xlsx found no entry under the supplied coding or protein notations; SupplementaryTables_V1.2.xlsx full text is unavailable and therefore remains a conversion gap. The explicit governing comparisons cannot be evaluated: OR not available ≥ 4? cannot evaluate; p-value not available ≤ 0.05? cannot evaluate; lower confidence interval not available excludes 2.0? cannot evaluate.

Rule
The prevalence of the variant in affected individuals is significantly increased compared to controls; case-control studies require p-value ≤0.05 and OR ≥4, with the lower confidence interval excluding 2.0.
Evidence considered
  • The ENIGMA BRCA2 specification states: 'Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0).'
  • The variant was normalized as NM_000059.4:c.8275del, NP_000050.3:p.(Val2759TrpfsTer18), and NP_000050.3:p.(V2759Wfs*18).
  • The searchable HUMU-40-1557-s001.xlsx text contains no exact entry for any supplied variant notation.
  • SupplementaryTables_V1.2.xlsx was declared for PS4, but its full text is unavailable; no variant-level lookup can be confirmed from that file.
Still missing
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in HUMU-40-1557-s001.xlsx.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in the searchable VCEP materials for SupplementaryTables_V1.2.xlsx; the full text of SupplementaryTables_V1.2.xlsx is unavailable and this is a conversion gap.
  • Variant-specific case and control counts, odds ratio, confidence interval, and p-value are unavailable.
Sources
cspec ↗vcep_humu_40_1557_s001vcep_supplementarytables_v1_2_2024_11_18
PM3 Not assessed: no Fanconi-anemia phenotype, second BRCA2 pathogenic variant, affected-proband observation, or phase information is documented for the required PM3 point calculation. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification applies PM3 only to a patient with phenotype consistent with BRCA1/2-related Fanconi anemia and a co-occurring pathogenic or likely pathogenic variant in the same gene. Table 6 assigns 1 point for unknown phase, 2 points for a confirmed or inferable pathogenic/likely pathogenic variant in trans or homozygous state, and PM3_Supporting, PM3, or PM3_Strong at totals of 1, 2, or at least 4 points, respectively. The case evidence documents no Fanconi-anemia phenotype or chromosome-breakage result, no affected proband observation with a second BRCA2 pathogenic/likely pathogenic variant, and no phase information. The variant is absent from gnomAD v2.1 and v4.1, satisfying the rarity prerequisite, but rarity alone cannot establish PM3.

Rule
Apply for a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and co-occurring variants in the same gene; PM3_Supporting = 1 point, PM3 = 2 points, PM3_Strong = 4 or more points.
Evidence considered
  • ENIGMA BRCA1/2 VCEP Specification v1.2 states that PM3 applies for a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and a co-occurring pathogenic or likely pathogenic variant in the same gene.
  • ENIGMA Table 6 assigns 1 point for unknown phase, 2 points for a pathogenic/likely pathogenic variant in trans or a homozygote with a consistent Fanconi-anemia phenotype, PM3_Supporting at 1 point, PM3 at 2 points, and PM3_Strong at 4 or more points.
  • The case evidence reports the target variant absent from gnomAD v2.1 and gnomAD v4.1, but contains no documented Fanconi-anemia phenotype, chromosome-breakage result, second BRCA2 pathogenic/likely pathogenic variant, affected-proband observation, or phase determination.
Still missing
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found when searched in Specifications_V1.2_2024-11-18.docx.txt; the file provides the governing PM3 rule but no variant-specific pre-assigned PM3 code.
  • Required data are missing: Fanconi-anemia phenotype or chromosome-breakage findings, a co-occurring BRCA2 pathogenic/likely pathogenic variant, affected-proband observations, and phase or homozygosity evidence.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PP1 Not assessed: no affected-relative segregation data or quantitative LR is available to compare with the PP1 threshold of LR >=2.08:1. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP permits PP1 only for co-segregation with disease in multiple affected family members measured by a quantitative co-segregation method, with PP1 Supporting at LR >=2.08:1, Moderate at LR >=4.3:1, Strong at LR >=18.7:1, and Very Strong at LR >=350:1. The case evidence bundle contains no proband-level family segregation observations, parental testing, affected-relative genotypes, meioses, or quantitative co-segregation LR for NM_000059.4:c.8275del (NP_000050.3:p.(Val2759TrpfsTer18)/p.(V2759Wfs*18)); therefore no PP1 strength can be assigned. The variant was not found in the searched full-text VCEP files Specifications_V1.2_2024-11-18.docx.txt or HUMU-40-1557-s001.xlsx.txt, and the declared SupplementaryTables_V1.2.xlsx full text is unavailable.

Rule
ENIGMA BRCA2 VCEP PP1_VariableWeight: assign strength by quantitative co-segregation LR; PP1 >=2.08:1, PP1_Moderate >=4.3:1, PP1_Strong >=18.7:1, PP1_Very Strong >=350:1.
Evidence considered
  • The ENIGMA BRCA2 VCEP PP1 rule requires quantitative co-segregation in multiple affected family members.
  • The VCEP PP1 LR thresholds are Supporting >=2.08:1, Moderate >=4.3:1, Strong >=18.7:1, and Very Strong >=350:1.
  • The case materials provide no segregation dataset or LR for this variant.
Still missing
  • No case-specific affected-relative genotypes, parental testing, meioses, phenotype-consistent family observations, or quantitative co-segregation LR were provided.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in HUMU-40-1557-s001.xlsx.txt.
  • SupplementaryTables_V1.2.xlsx is declared for BS4/PS4, but its full text is unavailable and could not be searched.
Sources
cspec ↗
PP4 Not assessed: no exact-variant combined clinical LR was found to compare with the ENIGMA PP4 supporting threshold of LR ≥2.08. Details ▾Hide ▴
Reasoning

The governing ENIGMA specification permits PP4 only for clinically calibrated multifactorial likelihood evidence and requires a combined LR ≥2.08 for supporting evidence, ≥4.3 for moderate, ≥18.7 for strong, or ≥350 for very strong. The exact-variant BRCA2 clinical-history table was searched for c.8275del and contains no matching row; the case bundle provides no combined clinical LR or component likelihoods for this variant. The explicit supporting comparison cannot be evaluated: LR not available ≥ 2.08? cannot evaluate. Therefore PP4 cannot be assigned.

Rule
Use ONLY to capture combined LR towards pathogenicity based on multifactorial likelihood clinical data; PP4 supporting requires LR ≥2.08:1, moderate ≥4.3:1, strong ≥18.7:1, and very strong ≥350:1.
Evidence considered
  • The ENIGMA specification states that PP4 is used only for combined LR towards pathogenicity based on multifactorial clinical data, with PP4 supporting at LR ≥2.08, moderate at LR ≥4.3, strong at LR ≥18.7, and very strong at LR ≥350.
  • The gene-specific PMID_31853058_BRCA2_clinical_history_LR.xlsx table was searched by exact Gene=BRCA2 and the supplied c.8275del notation; no exact row was found.
  • The Li et al. clinical-history model is governing methodology for this lookup, but no variant-level LR is available for this case.
Still missing
  • No exact BRCA2 c.8275del entry was found in PMID_31853058_BRCA2_clinical_history_LR.xlsx.
  • No combined clinical LR or calibrated phenotype/family-history component LRs are available for this variant.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗
BS2 Not assessed: no qualifying phenotyped individual, homozygote, trans co-occurrence, phase, or age-at-follow-up evidence was provided for the ENIGMA BS2 point system. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP applies BS2 only to documented phenotyped clinical or research-cohort individuals with the variant in trans with a pathogenic/likely pathogenic BRCA2 variant, as a homozygote, or with phase unknown, and assigns points according to age at cancer diagnosis or age at last follow-up; gnomAD homozygote observations must not be used for BS2 because frequency evidence is handled by BA1/BS1. The supplied case evidence contains no documented homozygote, trans co-occurrence, phase, age-at-follow-up, cancer history, or Fanconi Anemia phenotype assessment for this variant, so BS2 cannot be assigned.

Rule
ENIGMA BS2 variable-weight point system: Supporting = 1 point, Moderate = 2 points, Strong = >=4 points, using qualifying phenotyped clinical/research-cohort observations; do not use gnomAD frequency observations for BS2.
Evidence considered
  • ENIGMA BRCA2 v1.2 requires BS2 point assignment from qualifying individuals with trans pathogenic/likely pathogenic co-occurrence, homozygosity, or unknown phase, and final strength of Supporting at 1 point, Moderate at 2 points, or Strong at >=4 points.
  • The ENIGMA appendix explicitly excludes gnomAD homozygote observations from BS2 because frequency-based benign codes should capture those observations.
  • No qualifying individual-level BS2 evidence was present in the supplied case materials, and no variant-specific BS2 entry was found in the searched VCEP files.
Still missing
  • No variant-specific entry was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific entry was found in Appendices_V1.2_2024-11-18.docx.
  • The case evidence lacks qualifying BS2 clinical-cohort observations and age/follow-up data.
Sources
cspec ↗vcep_appendices_v1_2_2024_11_18
BS3 Not assessed: no governing VCEP Table 9 assignment or validated benign assay result reports BRCA2 c.8275del or p.(Val2759TrpfsTer18). Details ▾Hide ▴
Reasoning

Not assessed. The governing ENIGMA BRCA1/2 VCEP specification v1.2 applies BS3 to well-established functional assays showing no damaging effect on protein function, using protein-only or combined mRNA/protein assays, with calibrated variant-specific recommendations in Table 9; mRNA-only benign results use the alternative BP7 (RNA) framework. The exact variant NM_000059.4:c.8275del, p.(Val2759TrpfsTer18), and p.(V2759Wfs*18) was not found in Specifications_Table9_V1.2_2024-11-18.xlsx, which declares PS3/BS3 and contains calibrated assay assignments, nor in the other governing functional evidence files searched: Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, and HUMU-40-1557-s001.xlsx. The case-linked functional papers do not report a benign functional result for this exact variant; they describe BRCA2 biology or different truncating variants. Therefore there is no exact-variant calibrated functional result sufficient to assign BS3.

Rule
ENIGMA BS3: well-established in vitro or in vivo functional studies showing no damaging effect on protein function, using protein-only or combined mRNA/protein assays; use the calibrated Table 9 recommendation when available.
Evidence considered
  • ENIGMA VCEP v1.2 specifies BS3 for well-established functional studies showing no damaging effect on protein function using protein-only or combined mRNA/protein assays; mRNA-only benign results use BP7 (RNA).
  • Specifications_Table9_V1.2_2024-11-18.xlsx was searched under all three supplied variant notations and contained no exact-variant BS3 assignment.
  • Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, and HUMU-40-1557-s001.xlsx were each searched under c.8275del, p.Val2759TrpfsTer18, and p.V2759Wfs*18; no exact-variant functional entry was found.
  • PMID:11239455 reports damaging functional effects for other BRCA2-mutant cell lines, not a benign result for c.8275del.
  • PMID:10570174 reports localization of other BRCA2 truncation constructs, including 6174delT, not a benign result for c.8275del.
  • PMID:20878484 reports a different BRCA2 exon 15 insertion, 7525_7526insT, not a benign result for c.8275del.
  • PMID:22193408 and PMID:24312913 provide general BRCA2 functional context without an exact-variant benign assay result.
Still missing
  • No exact variant entry found in Specifications_Table9_V1.2_2024-11-18.xlsx after searching c.8275del, p.Val2759TrpfsTer18, and p.V2759Wfs*18.
  • No exact variant entry found in Specifications_V1.2_2024-11-18.docx after searching c.8275del, p.Val2759TrpfsTer18, and p.V2759Wfs*18.
  • No exact variant entry found in Appendices_V1.2_2024-11-18.docx after searching c.8275del, p.Val2759TrpfsTer18, and p.V2759Wfs*18.
  • No exact variant entry found in HUMU-40-1557-s001.xlsx after searching c.8275del, p.Val2759TrpfsTer18, and p.V2759Wfs*18.
  • No validated exact-variant protein or combined mRNA/protein functional assay result was identified in the case-linked literature.
  • The available exact-variant evidence is limited to predicted truncation/protein consequence and does not provide a BS3-calibrated functional measurement.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001vcep_specifications_table9_v1_2_2024_11_18PMID:10570174 ↗PMID:11239455 ↗PMID:20878484 ↗PMID:22193408 ↗PMID:24312913 ↗
BS4 Not assessed: no affected-family non-segregation data or quantitative LR is available to compare with the BS4 threshold of LR <=0.48. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP permits BS4 only for lack of segregation in affected family members measured by a quantitative co-segregation method, with BS4 Supporting for LR <=0.48, Moderate for LR <=0.23, Strong for LR <=0.05, and Very Strong for LR <=0.00285. The case evidence bundle contains no affected-family non-segregation observations, family genotypes, phenotype-consistent relatives, meioses, or quantitative LR for NM_000059.4:c.8275del (NP_000050.3:p.(Val2759TrpfsTer18)/p.(V2759Wfs*18)); therefore no BS4 strength can be assigned. The variant was not found in the searched full-text VCEP files Specifications_V1.2_2024-11-18.docx.txt or HUMU-40-1557-s001.xlsx.txt, and the declared SupplementaryTables_V1.2.xlsx full text is unavailable.

Rule
ENIGMA BRCA2 VCEP BS4_VariableWeight: assign strength by quantitative non-segregation LR; BS4_Supporting <=0.48, BS4_Moderate <=0.23, BS4 <=0.05, BS4_Very Strong <=0.00285.
Evidence considered
  • The ENIGMA BRCA2 VCEP BS4 rule requires quantitative lack-of-segregation evidence in affected family members.
  • The VCEP BS4 LR thresholds are Supporting <=0.48, Moderate <=0.23, Strong <=0.05, and Very Strong <=0.00285.
  • The case materials provide no non-segregation dataset or LR for this variant.
Still missing
  • No case-specific affected-family non-segregation observations, genotypes, parental testing, meioses, or quantitative co-segregation LR were provided.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in HUMU-40-1557-s001.xlsx.txt.
  • SupplementaryTables_V1.2.xlsx is declared for BS4/PS4, but its full text is unavailable and could not be searched.
Sources
cspec ↗
BP5 Not assessed: no exact-variant combined clinical LR was available to evaluate BP5's required LR ≤0.48 comparison. Details ▾Hide ▴
Reasoning

The governing ENIGMA specification restricts BP5 to combined multifactorial clinical LR against pathogenicity: supporting requires LR ≤0.48 and >0.23, moderate requires LR ≤0.23, strong requires LR ≤0.05, and very strong requires LR ≤0.00285; combined LR >0.48 to 1.00 is not informative. The exact-variant BRCA2 clinical-history table was searched for c.8275del and contains no matching row, and no combined clinical LR or component LRs are present in the case evidence. The explicit supporting comparison cannot be evaluated: LR not available ≤ 0.48? cannot evaluate. Therefore BP5 cannot be assigned.

Rule
Use ONLY to capture combined LR against pathogenicity based on multifactorial likelihood clinical data; BP5 supporting requires LR ≤0.48 and >0.23:1, moderate ≤0.23:1, strong ≤0.05:1, and very strong ≤0.00285:1.
Evidence considered
  • The ENIGMA specification states that BP5 is used only for combined LR against pathogenicity based on multifactorial clinical data: supporting LR ≤0.48 and >0.23, moderate LR ≤0.23, strong LR ≤0.05, and very strong LR ≤0.00285; LR >0.48 to 1.00 is not informative.
  • The gene-specific PMID_31853058_BRCA2_clinical_history_LR.xlsx table was searched by exact Gene=BRCA2 and the supplied c.8275del notation; no exact row was found.
  • Easton et al. provides methodology/context for multifactorial likelihood assessment, but no exact-variant BP5 LR is available and no value is inferred from that methodology.
Still missing
  • No exact BRCA2 c.8275del entry was found in PMID_31853058_BRCA2_clinical_history_LR.xlsx.
  • No combined clinical LR or calibrated phenotype/family-history component LRs are available for this variant.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗PMID:17924331 ↗
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: the variant is a frameshift, whereas ENIGMA PS1 applies to an identical missense change or precisely matched splice event. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification limits PS1 to the same missense substitution or a precisely matched splice event relative to an established pathogenic or likely pathogenic reference variant. NM_000059.4:c.8275del is a frameshift, predicted to produce p.(Val2759TrpfsTer18), and no governing VCEP file contains an exact entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18; therefore PS1 is not applicable.

Rule
ENIGMA BRCA2 PS1 applies to identical missense substitutions or precisely matched splice events, not generic frameshift consequences.
Evidence considered
  • ENIGMA Appendix J defines PS1 for the same missense substitution as an established pathogenic variant or for a precisely matched predicted splice event.
  • The normalized consequence is a frameshift, NM_000059.4:c.8275del, producing p.(Val2759TrpfsTer18), not a missense substitution.
Still missing
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PS2 VCEPNot applicable: the ENIGMA BRCA2 VCEP explicitly prohibits PS2 because de novo occurrences are not calibrated for these relatively common cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP specification explicitly states that PS2 should not be used for BRCA1/2-related cancers because these cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences. No case-specific de novo observation can override this governing rule.

VCEP rule
ENIGMA BRCA2 VCEP PS2: Do not use.
Evidence considered
  • Specifications V1.2 Table 1 states for PS2: "Do not use"; the stated reason is that BRCA1/2-related cancers occur relatively commonly and de novo predictive capacity is not calibrated.
Sources
cspec ↗
PM1 VCEPNot applicable: ENIGMA designates PM1 as not applicable, and this variant is a frameshift rather than a domain-assessed missense alteration. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly designates PM1 as not applicable and evaluates domain-related information through calibrated bioinformatic criteria for missense alterations. The variant is a frameshift at codon 2759, and vcep_materials.json has no domain_tables entry for BRCA2 requiring an authoritative residue check; therefore PM1 is not applicable.

VCEP rule
ENIGMA BRCA2 PM1 is not applicable; domain information is incorporated into calibrated bioinformatic evaluation of eligible missense alterations.
Evidence considered
  • ENIGMA Table 1 states that PM1 is not used for BRCA2 and is considered within calibrated bioinformatic analysis instead.
  • The BRCA2 domain_tables object is empty, and the variant consequence is a frameshift rather than a missense alteration for which domain-based PM1 analysis is defined.
Still missing
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
PM2 N/ANot applicable: ENIGMA excludes PM2 for deletion variants, despite the variant being absent from gnomAD v2.1 and v3.1 non-cancer datasets. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 VCEP limits PM2 to Supporting strength for absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes with regional read depth >=25, but explicitly states that PM2 must not be applied to insertion, deletion, or delins variants. This variant is a deletion, so PM2 is not applicable even though the case evidence reports it absent from the specified gnomAD non-cancer datasets. No variant-specific row for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx.

Rule
ENIGMA PM2_Supporting: absent from qualifying gnomAD non-cancer datasets with regional read depth >=25, but not applicable to insertion, deletion, or delins variants.
Evidence considered
  • ENIGMA BRCA2 v1.2 defines PM2_Supporting using absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, requires regional read depth >=25, and explicitly excludes insertion, deletion, and delins variants.
  • The case evidence identifies NM_000059.4:c.8275del as a deletion and reports it absent from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer.
  • The governing VCEP files were searched under all three supplied variant notations; no variant-specific population entry was found.
Still missing
  • No variant-specific entry was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific entry was found in Appendices_V1.2_2024-11-18.docx.
  • No variant-specific entry was found in HUMU-40-1557-s001.xlsx.
  • The case evidence does not provide the regional read-depth value, which would be required even for an eligible variant type.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001
PM4 VCEPNot applicable: c.8275del is a frameshift with a premature stop, while ENIGMA excludes PM4 and limits it to in-frame length changes or stop-loss variants. Details ▾Hide ▴
Reasoning

The variant is a frameshift producing a premature termination codon, not an in-frame insertion/deletion or a stop-loss variant. The governing ENIGMA BRCA1/2 V1.2 specification explicitly states that PM4 is not used and that relevant in-frame protein-length-change considerations are captured through bioinformatic analysis. Therefore PM4 is not applicable to this variant.

VCEP rule
ENIGMA BRCA1/2 V1.2 Table 1: PM4 do not use; protein length changes due to in-frame insertions/deletions or stop-loss are handled as part of bioinformatic analysis.
Evidence considered
  • The normalized consequence is frameshift with premature termination, not an in-frame insertion/deletion or stop-loss change.
  • ENIGMA V1.2 Table 1 states PM4 is not used and that protein-length-change information is considered through bioinformatic analysis.
Still missing
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry was found in Specifications_V1.2_2024-11-18.docx; the explicit VCEP PM4 exclusion governs.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry was found in Appendices_V1.2_2024-11-18.docx; no PM4-specific variant row was required.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx; Table 4 is a PVS1/PM5 table and does not govern PM4.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf; the paper is not needed for PM4 because the VCEP rule makes PM4 not applicable.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM6 VCEPNot applicable: the ENIGMA BRCA2 VCEP explicitly prohibits PM6 because uncalibrated de novo occurrences cannot provide validated evidence. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP specification explicitly states that PM6 should not be used for confirmed de novo occurrences without confirmation of paternity and maternity, for the same lack of calibration in BRCA1/2-related cancers. No case-specific de novo observation can override this governing rule.

VCEP rule
ENIGMA BRCA2 VCEP PM6: Do not use.
Evidence considered
  • Specifications V1.2 Table 1 states for PM6: "Do not use"; the stated reason is that BRCA1/2-related cancers occur relatively commonly and de novo predictive capacity is not calibrated.
Sources
cspec ↗
PP2 VCEPNot applicable: ENIGMA excludes PP2 for BRCA2 because missense variants are not a common disease mechanism, and this variant is a frameshift. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly states that PP2 is not applicable because missense variants are not a common mechanism of pathogenicity for BRCA1 and BRCA2. This case is additionally a frameshift rather than a missense variant.

VCEP rule
Do not apply PP2 for BRCA2; the VCEP specifies that missense variants are not a common pathogenic mechanism.
Evidence considered
  • ENIGMA Table 1 and Appendix J designate PP2 as not applicable because missense variants are not a common mechanism of pathogenicity in BRCA1 or BRCA2.
  • The assessed variant is a frameshift, not a missense variant.
Still missing
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP3 N/ANot applicable: c.8275del is a frameshift, outside ENIGMA's PP3 computational-evidence scope for missense, in-frame, or splice-region variants. Details ▾Hide ▴
Reasoning

Not applicable: NM_000059.4:c.8275del is a frameshift variant producing p.(Val2759TrpfsTer18), and the ENIGMA BRCA2 v1.2 specification limits PP3 to missense/in-frame variants or splice-impact assessment of silent, missense/in-frame, or intronic variants; computational predictor scores must not be evaluated for this truncating variant.

Rule
ENIGMA BRCA2 v1.2 PP3: apply for missense or in-frame insertion, deletion, or delins variants inside a potentially clinically important functional domain with BayesDel no-AF >= 0.30, or for predicted splicing with SpliceAI >= 0.2 in silent, missense/in-frame, or intronic variants outside donor and acceptor +/-1,2 sites.
Evidence considered
  • The case normalization identifies NM_000059.4:c.8275del as a frameshift producing NP_000050.3:p.(Val2759TrpfsTer18) / p.(V2759Wfs*18).
  • ENIGMA BRCA2 v1.2 specifies PP3 for missense or in-frame variants with protein-impact evidence, and for splice predictions involving silent, missense/in-frame, or intronic variants; truncating frameshifts are outside this criterion's scope.
Still missing
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗
PP5 VCEPNot applicable: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic assertion for c.8275del. Details ▾Hide ▴
Reasoning

PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. The case evidence states that NM_000059.4:c.8275del is absent from ClinVar, with no variation ID, classification, review status, or expert-panel assertion. Ordinary laboratory submissions, aggregate labels, and non-expert assertions therefore cannot trigger PP5; no qualifying assertion exists.

VCEP rule
Apply PP5 only for an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic; ordinary laboratory, aggregate, and non-expert assertions do not qualify.
Evidence considered
  • The case ClinVar search reports no exact result for NM_000059.4:c.8275del and no variation ID, classification, review status, or expert-panel assertion.
  • The ENIGMA VCEP specification labels PP5 not applicable, and this adjudication applies PP5 only when the exact variant has a ClinVar expert-panel Pathogenic or Likely pathogenic classification.
Still missing
  • No exact-variant ClinVar record or expert-panel classification was found.
Sources
clinvar ↗cspec ↗
BP1 N/ANot applicable: BP1 requires a silent, missense, or in-frame indel outside a domain, but c.8275del is a frameshift despite SpliceAI 0.095. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 BP1 rule is restricted to silent, missense, or in-frame insertion/deletion variants outside a clinically important functional domain with SpliceAI at or below 0.1. NM_000059.4:c.8275del is a frameshift, so BP1 is not applicable even though the recorded SpliceAI maximum delta is 0.095.

Rule
Apply BP1_Strong only to eligible silent, missense, or in-frame insertion-deletion variants outside a clinically important domain with SpliceAI ≤0.1; frameshifts are excluded.
Evidence considered
  • ENIGMA Appendix J restricts BP1_Strong to silent, missense, or in-frame insertion-deletion variants outside a clinically important domain with SpliceAI ≤0.1.
  • The case evidence reports SpliceAI maximum delta 0.095, but the variant consequence is a frameshift, which is outside the BP1-eligible variant classes.
Still missing
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
Sources
cspec ↗spliceai ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
BP2 VCEPNot applicable: ENIGMA BRCA2 explicitly does not use BP2 independently and restricts it to the context of BS2. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification explicitly states that BP2 is not used and is applied only in the context of BS2. BP2 therefore cannot be assigned as an independent benign criterion for this BRCA2 frameshift variant, regardless of whether cis or trans observations might otherwise be available.

VCEP rule
Do not use; applied only in the context of BS2.
Evidence considered
  • ENIGMA BRCA1/2 VCEP Specification v1.2 Table 1 marks BP2 as do not use and states that it is applied only in the context of BS2.
  • The structured ENIGMA VCEP rule for BP2 marks the criterion not applicable and does not provide any permitted strength.
Sources
cspec ↗
BP3 VCEPNot applicable: c.8275del is a premature-termination frameshift, whereas ENIGMA excludes BP3 and limits it to in-frame changes in repetitive regions without known function. Details ▾Hide ▴
Reasoning

The variant is a frameshift that introduces a premature termination codon, not an in-frame deletion or insertion. The governing ENIGMA BRCA1/2 V1.2 specification explicitly states that BP3 is not used and that repetitive-region/domain considerations are captured by bioinformatic analysis. Consequently BP3 is not applicable, regardless of whether the affected sequence is repetitive.

VCEP rule
ENIGMA BRCA1/2 V1.2 Table 1: BP3 do not use; in-frame insertions/deletions in repetitive regions without known function are captured by bioinformatic and domain analysis.
Evidence considered
  • The normalized consequence is a frameshift with premature termination, not an in-frame insertion/deletion.
  • ENIGMA V1.2 Table 1 states BP3 is not used and that repetitive-region/domain analysis is captured by bioinformatic analysis.
Still missing
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry was found in Specifications_V1.2_2024-11-18.docx; the explicit VCEP BP3 exclusion governs.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry was found in Appendices_V1.2_2024-11-18.docx; no BP3-specific variant row was required.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx; Table 4 is a PVS1/PM5 table and does not govern BP3.
  • No exact c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf; the paper is not needed for BP3 because the VCEP rule makes BP3 not applicable.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP4 N/ANot applicable: c.8275del is a frameshift, outside ENIGMA's BP4 computational-evidence scope for missense, silent, or qualifying intronic variants. Details ▾Hide ▴
Reasoning

Not applicable: NM_000059.4:c.8275del is a frameshift variant producing p.(Val2759TrpfsTer18), and the ENIGMA BRCA2 v1.2 specification limits BP4 to missense/in-frame variants, silent variants in the specified domain, or qualifying intronic variants; computational predictor scores must not be evaluated for this truncating variant.

Rule
ENIGMA BRCA2 v1.2 BP4: apply for missense or in-frame insertion, deletion, or delins variants in a potentially clinically important domain with BayesDel no-AF <= 0.18 and SpliceAI <= 0.1, or qualifying silent/intronic variants with SpliceAI <= 0.1.
Evidence considered
  • The case normalization identifies NM_000059.4:c.8275del as a frameshift producing NP_000050.3:p.(Val2759TrpfsTer18) / p.(V2759Wfs*18).
  • ENIGMA BRCA2 v1.2 specifies BP4 for missense/in-frame variants, silent variants in a potentially clinically important domain, or intronic variants outside canonical splice positions when computational evidence predicts no impact; truncating frameshifts are outside this criterion's scope.
Still missing
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗
BP6 VCEPNot applicable: ClinVar has no exact-variant expert-panel Benign or Likely benign assertion for c.8275del. Details ▾Hide ▴
Reasoning

BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. The case evidence states that NM_000059.4:c.8275del is absent from ClinVar, with no variation ID, classification, review status, or expert-panel assertion. Ordinary laboratory submissions, aggregate labels, and non-expert assertions therefore cannot trigger BP6; no qualifying assertion exists.

VCEP rule
Apply BP6 only for an exact-variant ClinVar expert-panel classification of Benign or Likely benign; ordinary laboratory, aggregate, and non-expert assertions do not qualify.
Evidence considered
  • The case ClinVar search reports no exact result for NM_000059.4:c.8275del and no variation ID, classification, review status, or expert-panel assertion.
  • The ENIGMA VCEP specification labels BP6 not applicable, and this adjudication applies BP6 only when the exact variant has a ClinVar expert-panel Benign or Likely benign classification.
Still missing
  • No exact-variant ClinVar record or expert-panel classification was found.
Sources
clinvar ↗cspec ↗
BP7 N/ANot applicable: c.8275del is a frameshift, whereas ENIGMA's BP7 scope is limited to synonymous or qualifying intronic variants. Details ▾Hide ▴
Reasoning

Not applicable: NM_000059.4:c.8275del is a frameshift variant, not a synonymous variant; ENIGMA BRCA2 v1.2 BP7 applies only to qualifying synonymous or intronic variants, so SpliceAI and conservation evidence were not evaluated.

Rule
ENIGMA BRCA2 v1.2 BP7: apply to a synonymous variant inside a potentially clinically important functional domain if BP4 is met, or to an intronic variant at or beyond positions +7/-21 outside conserved donor or acceptor motifs if BP4 is met.
Evidence considered
  • The case normalization identifies NM_000059.4:c.8275del as a frameshift producing NP_000050.3:p.(Val2759TrpfsTer18) / p.(V2759Wfs*18).
  • ENIGMA BRCA2 v1.2 limits BP7 to synonymous variants in the specified context or qualifying intronic variants, with BP4 met; a frameshift is outside BP7 scope.
Still missing
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗

Identifiers

Gene
BRCA2
Transcript
NM_000059.4
Coding (HGVS c.)
NM_000059.4:c.8275del
Protein (HGVS p.)
NP_000050.3:p.(Val2759TrpfsTer18)
GRCh38
chr13:32363475 TG>T
GRCh37
chr13:32937612 TG>T
Location and type
Exon 18 · frameshift

Gene diagram

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…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele 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 +442 bp
0.018
SpliceAI acceptor gainat -60 bp
0.002
SpliceAI donor lossat +58 bp
0.095
SpliceAI donor gainat -99 bp
0.002
Pangolin splice lossmagnitude shown
-0.054
Pangolin splice gain
0.003

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ANot applicable: c.8275del is a frameshift, outside ENIGMA's PP3 computational-evidence scope for missense, in-frame, or splice-region variants. Details ▾Hide ▴
Reasoning

Not applicable: NM_000059.4:c.8275del is a frameshift variant producing p.(Val2759TrpfsTer18), and the ENIGMA BRCA2 v1.2 specification limits PP3 to missense/in-frame variants or splice-impact assessment of silent, missense/in-frame, or intronic variants; computational predictor scores must not be evaluated for this truncating variant.

Rule
ENIGMA BRCA2 v1.2 PP3: apply for missense or in-frame insertion, deletion, or delins variants inside a potentially clinically important functional domain with BayesDel no-AF >= 0.30, or for predicted splicing with SpliceAI >= 0.2 in silent, missense/in-frame, or intronic variants outside donor and acceptor +/-1,2 sites.
Evidence considered
  • The case normalization identifies NM_000059.4:c.8275del as a frameshift producing NP_000050.3:p.(Val2759TrpfsTer18) / p.(V2759Wfs*18).
  • ENIGMA BRCA2 v1.2 specifies PP3 for missense or in-frame variants with protein-impact evidence, and for splice predictions involving silent, missense/in-frame, or intronic variants; truncating frameshifts are outside this criterion's scope.
Still missing
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗
BP4 N/ANot applicable: c.8275del is a frameshift, outside ENIGMA's BP4 computational-evidence scope for missense, silent, or qualifying intronic variants. Details ▾Hide ▴
Reasoning

Not applicable: NM_000059.4:c.8275del is a frameshift variant producing p.(Val2759TrpfsTer18), and the ENIGMA BRCA2 v1.2 specification limits BP4 to missense/in-frame variants, silent variants in the specified domain, or qualifying intronic variants; computational predictor scores must not be evaluated for this truncating variant.

Rule
ENIGMA BRCA2 v1.2 BP4: apply for missense or in-frame insertion, deletion, or delins variants in a potentially clinically important domain with BayesDel no-AF <= 0.18 and SpliceAI <= 0.1, or qualifying silent/intronic variants with SpliceAI <= 0.1.
Evidence considered
  • The case normalization identifies NM_000059.4:c.8275del as a frameshift producing NP_000050.3:p.(Val2759TrpfsTer18) / p.(V2759Wfs*18).
  • ENIGMA BRCA2 v1.2 specifies BP4 for missense/in-frame variants, silent variants in a potentially clinically important domain, or intronic variants outside canonical splice positions when computational evidence predicts no impact; truncating frameshifts are outside this criterion's scope.
Still missing
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗
BP7 N/ANot applicable: c.8275del is a frameshift, whereas ENIGMA's BP7 scope is limited to synonymous or qualifying intronic variants. Details ▾Hide ▴
Reasoning

Not applicable: NM_000059.4:c.8275del is a frameshift variant, not a synonymous variant; ENIGMA BRCA2 v1.2 BP7 applies only to qualifying synonymous or intronic variants, so SpliceAI and conservation evidence were not evaluated.

Rule
ENIGMA BRCA2 v1.2 BP7: apply to a synonymous variant inside a potentially clinically important functional domain if BP4 is met, or to an intronic variant at or beyond positions +7/-21 outside conserved donor or acceptor motifs if BP4 is met.
Evidence considered
  • The case normalization identifies NM_000059.4:c.8275del as a frameshift producing NP_000050.3:p.(Val2759TrpfsTer18) / p.(V2759Wfs*18).
  • ENIGMA BRCA2 v1.2 limits BP7 to synonymous variants in the specified context or qualifying intronic variants, with BP4 met; a frameshift is outside BP7 scope.
Still missing
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.8275del, p.Val2759TrpfsTer18, or p.V2759Wfs*18 was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).

5 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

  • Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.
    The paper does not report BRCA2 c.8275del or p.(V2759Wfs*18). It describes other BRCA2 truncation constructs and shows that loss of the terminal nuclear-localization region produces predominantly cytoplasmic, nucleus-excluded protein.
    Does not name this variant
    PMID 10570174 ↗
    Quoted passage
    In summary, within the final 156 amino acids of BRCA2 reside NLS1 and NLS3, the two functional NLSs of BRCA2.

    Results, “BRCA2 NLSs Reside in the Extreme C Terminus”

  • BRCA2 is required for homology-directed repair of chromosomal breaks.
    The paper does not mention BRCA2 c.8275del or p.(V2759Wfs*18). It reports impaired homology-directed repair in cell lines carrying other BRCA2 alterations, including 6174delT and engineered C-terminal deletions.
    Does not name this variant
    PMID 11239455 ↗
    Quoted passage
    BRCA2 mutant cell lines are recombination deficient, such that homology-directed repair is reduced 6- to .100-fold, depending on the cell line.

    Summary; Results, “BRCA2-Deficient CAPAN-1 Cells Are Defective in HDR”

  • A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.
    The paper does not mention BRCA2 c.8275del or p.(V2759Wfs*18). It reports a different BRCA2 exon 15 insertion, 7525_7526insT, causing a frameshift and premature stop codon.
    Does not name this variant
    PMID 20878484 ↗
    Quoted passage
    In this study, we have identified in a Italian healthy woman a pathological mutation in exon 15, the 7525_7526insT ... that causes a frame shift [p.Ser2509fs], resulting in a stop codon 29 amino acids downstream.

    Results, first paragraph

  • BRCA1 and BRCA2: different roles in a common pathway of genome protection.
    The paper does not mention BRCA2 c.8275del or NP_000050.3:p.(V2759Wfs*18) specifically. It describes BRCA2 as a tumour-suppressor protein whose primary function is homologous recombination-mediated DNA repair, including RAD51 recruitment and protection of nascent DNA at stalled replication forks.
    Does not name this variant
    PMID 22193408 ↗
    Quoted passage
    Overwhelming evidence suggests that the primary function of BRCA2 is to facilitate HR (TABLE 1). BRCA2-deficient cells are defective in recruiting RAD51 to sites of DSBs and in repairing DSBs by HR60.

    Section: “BRCA2, HR and replication fidelity”

  • A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.
    The paper does not explicitly mention BRCA2 c.8275del or p.(V2759Wfs*18). It generally describes BRCA2 insertions/deletions that introduce premature stop codons and notes critical C-terminal functional regions.
    Does not name this variant
    PMID 24312913 ↗
    Quoted passage
    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”

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.095 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

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.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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.