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BRCA2c.9257G>CLikely benign
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Variant interpretation report

BRCA2 c.9257G>C, p.(Gly3086Ala)

NM_000059.4:c.9257G>C NP_000050.3:p.(Gly3086Ala) Missense · exon 25 View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

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

Likely benign.A likely benign 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: 0 Benign evidence criteria: 2
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 2
BS1Strong
BS1 · strong

Met at strong: maximum non-cancer grpmax FAF was 0.00043582, exceeding the ENIGMA BS1 threshold of 0.0001.

BP4Supporting
BP4 · supporting

Met, Supporting: BayesDel -0.0288497 is <=0.18 and SpliceAI 0.011 is <=0.1, satisfying both BRCA2 BP4 no-impact requirements.

Recorded classification: Likely benign

Likely Benign: BS1 (strong) plus BP4 (supporting) satisfy the ENIGMA BRCA2 VCEP Table 3 Strong(Benign)+Supporting(Benign) 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
48 / 1,612,568 alleles

gnomAD v4.1: 48 / 1,612,568 alleles. Recorded AF 2.97662e-05. Recorded homozygote count 1.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 8.00576e-05; MAF= 0.00801%, 20/249820 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000656858; MAF= 0.06569%, 20/30448 alleles, homozygotes = 1); grpmax FAF= 0.00043457.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · BS1 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
No screenshot for this evidence
REVEL score
0.619 recorded score

Recorded REVEL score: 0.619. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 →
ClinVar submissions
13 reported laboratory submissions

6 Uncertain significance · 4 Likely benign · 2 Benign · 1 Uncertain Significance. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

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 · 4 not met · 9 not assessed · 13 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

All three requested criteria are not applicable under the ENIGMA BRCA2 VCEP specification: PVS1 is restricted to null variants, while PM4 and BP3 are explicitly marked Do not use.

The variant is NM_000059.4:c.9257G>C, an exon 25 missense substitution p.(Gly3086Ala); the exact-variant mRNA study found no observed splicing effect.

No requested criterion was assigned from generic ACMG/AMP thresholds or from a final classification; the ENIGMA VCEP rules govern.

The exact variant was searched under c.9257G>C, p.Gly3086Ala, and p.G3086A in the named governing VCEP full-text files.

The ENIGMA BRCA2 computational scope was settled before applying scores: PP3 and BP4 use BayesDel plus SpliceAI for missense variants inside the DNA-binding domain; BP7 does not cover this missense variant because it is inside that domain.

PP3 is not met because BayesDel -0.0288497 is below 0.30 and SpliceAI 0.011 is below 0.2. BP4 is met at Supporting strength because BayesDel -0.0288497 is <=0.18 and SpliceAI 0.011 is <=0.1. BP7 is not applicable by scope.

Population evidence supports BS1 Strong because the maximum governing non-cancer filter allele frequency is 0.00043582, above 0.0001 but below the BA1 threshold of 0.001.

BA1 and PM2 are not met; BS2 is not assessed because the only homozygote observation is from population data without the VCEP-required phenotypic and age/follow-up information.

Met · 2

BS1 StrongVCEPMet at strong: maximum non-cancer grpmax FAF was 0.00043582, exceeding the ENIGMA BS1 threshold of 0.0001. Details ▾Hide ▴
Reasoning

BS1 Strong is met. The ENIGMA rule assigns Strong BS1 when maximum filter allele frequency is above 0.0001 in a non-founder population using gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes. The maximum reported non-cancer grpmax FAF was 0.00043582 in gnomAD v2.1 non-cancer exomes and 0.00028352 in gnomAD v3.1 non-cancer genomes; both exceed 0.0001. The higher value, 0.00043582, governs the strength and is below the separate BA1 threshold of 0.001.

VCEP rule
Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.
Evidence considered
  • gnomAD v2.1 non-cancer exomes: maximum non-cancer grpmax FAF 0.00043582, from 20 alternate alleles among 235466, with one homozygote.
  • gnomAD v3.1 non-cancer genomes: maximum non-cancer grpmax FAF 0.00028352, from 4 alternate alleles among 147624, with zero homozygotes.
  • The governing ENIGMA BRCA2 specification assigns BS1 Strong above FAF 0.0001 and BS1 Supporting only above 0.00002 through 0.0001.
Still missing
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingVCEPMet, Supporting: BayesDel -0.0288497 is <=0.18 and SpliceAI 0.011 is <=0.1, satisfying both BRCA2 BP4 no-impact requirements. Details ▾Hide ▴
Reasoning

The variant is a missense substitution inside the BRCA2 DNA-binding domain (aa 2481-3186), so BP4 requires both no predicted protein impact and no predicted splice impact. BayesDel no-AF is -0.0288497, which is at or below the VCEP BRCA2 no-impact cutoff of 0.18, and SpliceAI maximum delta is 0.011, which is at or below 0.1. Both required components are met, so BP4 is met at Supporting strength. The exact variant was not found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

VCEP rule
Apply BP4 for: ... Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel predicted No Impact AND SpliceAI ≤0.1). ... BRCA2: No impact ≤ 0.18
Evidence considered
  • The ENIGMA VCEP defines BP4 for missense variants inside a clinically important functional domain only when BayesDel predicts no impact and SpliceAI is <=0.1; BRCA2 no-impact BayesDel cutoff is 0.18.
  • BayesDel no-AF score for NM_000059.4:c.9257G>C is -0.0288497, meeting the VCEP BRCA2 no-impact cutoff of <=0.18.
  • SpliceAI maximum delta score is 0.011, meeting the VCEP no-predicted-splicing cutoff of <=0.1.
  • Wangensteen et al. 2019 mRNA assay explicitly lists BRCA2 c.9257G > C p.(Gly3086Ala) in Table 2 and classifies it as splice class 1S with no observed splicing effect; this is concordant supporting context, not a replacement for the governing SpliceAI rule.
Still missing
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗bayesdelspliceai ↗PMID:31143303 ↗

Not met · 4 · evaluated, threshold not reached

PM2 VCEPNot met: the variant is present in gnomAD v2.1 non-cancer exomes at AF 8.4938e-05 and gnomAD v3.1 non-cancer genomes at AF 2.7096e-05. Details ▾Hide ▴
Reasoning

PM2 Supporting is not met because the variant is present in both governing non-cancer control datasets. gnomAD v2.1 non-cancer exomes report 20/235466 alleles and one homozygote; gnomAD v3.1 non-cancer genomes report 4/147624 alleles and zero homozygotes. Therefore the variant is not absent from controls, irrespective of the VCEP read-depth requirement.

VCEP rule
Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.
Evidence considered
  • gnomAD v2.1 non-cancer exomes: variant present at AF 8.4937952825461e-05, 20/235466 alleles, homozygotes = 1.
  • gnomAD v3.1 non-cancer genomes: variant present at AF 2.709586517097491e-05, 4/147624 alleles, homozygotes = 0.
  • The governing ENIGMA rule requires the variant to be absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with local average read depth ≥25.
Still missing
  • The available case evidence does not report average local read depth; however, PM2 is not met because the variant is observed in both required control datasets.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PM3 VCEPNot met: gnomAD maximum FAF is 0.00043457, exceeding the VCEP benign-evidence threshold of 0.0001, and no Fanconi-anemia proband with a same-gene co-occurring variant is documented. Details ▾Hide ▴
Reasoning

The VCEP restricts PM3 to a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and a co-occurrent variant in the same gene, and requires the variant under assessment to be sufficiently rare (not meeting a benign population evidence code). No affected-proband record, Fanconi anemia phenotype, same-gene pathogenic variant, or phase information for c.9257G>C was found in the case evidence. In addition, gnomAD v2.1 and v4.1 report maximum population FAF values of 0.00043457 and 0.00040896, respectively, both above the VCEP BS1 threshold of 0.0001, so the rarity prerequisite is not satisfied.

VCEP rule
Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. ... Variant under assessment must be sufficiently rare (not meeting a benign population evidence code).
Evidence considered
  • ENIGMA BRCA2 specification v1.2, Table 1/PM3: PM3 applies only to a patient with a BRCA1/2-related Fanconi anemia phenotype and a co-occurrent variant in the same gene; the assessed variant must be sufficiently rare and must not meet a benign population evidence code.
  • Case evidence bundle: no affected-proband Fanconi anemia presentation, same-gene pathogenic variant, trans/cis phase, or other allelic observation was documented for BRCA2 c.9257G>C (p.Gly3086Ala; p.G3086A).
  • gnomAD v2.1: maximum filter allele frequency (grpmax FAF) 0.00043457; gnomAD v4.1: maximum filter allele frequency (grpmax FAF) 0.00040896. The VCEP BS1 rule defines benign population evidence as FAF > 0.0001.
Still missing
  • No affected-proband, Fanconi anemia phenotype, same-gene pathogenic-variant, or phase observation for this variant was available in the case evidence bundle.
  • No entry for c.9257G>C, p.Gly3086Ala, or p.G3086A was found in Specifications_V1.2_2024-11-18.docx.txt or the BRCA2 fulltext files searched.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PP3 VCEPNot met: BayesDel -0.0288497 is below the 0.30 PP3 threshold and SpliceAI 0.011 is below the 0.2 splice threshold. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, and p.Gly3086Ala lies within the BRCA2 DNA-binding domain (aa 2481-3186), so the VCEP PP3 protein-impact pathway is in scope. BayesDel no-AF is -0.0288497, below the BRCA2 PP3 impact threshold of 0.30. The independent VCEP splicing pathway is also not met: the SpliceAI maximum delta score is 0.011, below the PP3 threshold of 0.2. Therefore PP3 is not met; the same SpliceAI result is not counted again for BP4. The exact variant was not found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

VCEP rule
Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel predicted Impact). ... Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor ±1,2 positions.
Evidence considered
  • The case normalization identifies NM_000059.4:c.9257G>C as NP_000050.3:p.(Gly3086Ala), a missense variant at amino acid 3086; the ENIGMA BRCA2 DNA-binding domain is aa 2481-3186.
  • BayesDel no-AF score for the exact variant is -0.0288497. The VCEP Appendix J BRCA2 PP3 impact threshold is BayesDel >=0.30; this score does not meet it.
  • SpliceAI scores for NM_000059.4:c.9257G>C are DS_AG 0.011, DS_AL 0.003, DS_DG 0.0, and DS_DL 0.003; maximum delta score is 0.011. The VCEP PP3 splicing threshold is SpliceAI >=0.2; this result does not meet it.
  • The VCEP-governing files were searched for c.9257G>C, p.Gly3086Ala, and p.G3086A; no exact variant-level pre-assigned PP3 code was found.
Still missing
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗bayesdelspliceai ↗
BA1 VCEPNot met: maximum non-cancer grpmax FAF was 0.00043582, below the ENIGMA BA1 threshold of 0.001. Details ▾Hide ▴
Reasoning

BA1 is not met. The ENIGMA rule requires maximum filter allele frequency above 0.001 in a non-founder population, using gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes. The maximum reported non-cancer grpmax FAF was 0.00043582 in gnomAD v2.1 non-cancer exomes and 0.00028352 in gnomAD v3.1 non-cancer genomes, both below 0.001. The variant was observed once in the gnomAD v2.1 non-cancer exome dataset and zero times homozygous in gnomAD v3.1 non-cancer genomes; this does not reach the BA1 frequency threshold.

VCEP rule
Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.
Evidence considered
  • gnomAD v2.1 non-cancer exomes: 20/235466 alleles, AF 8.4937952825461e-05, one homozygote, maximum non-cancer grpmax FAF 0.00043582.
  • gnomAD v3.1 non-cancer genomes: 4/147624 alleles, AF 2.709586517097491e-05, zero homozygotes, maximum non-cancer grpmax FAF 0.00028352.
  • The governing ENIGMA BRCA2 specification identifies gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes as the preferred datasets and requires BA1 FAF >0.001.
Still missing
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 9 · no assessment recorded

PS1 VCEPNot assessed: SpliceAI max delta 0.011 meets the <=0.1 requirement, but no qualifying pathogenic same-amino-acid reference variant was found. Details ▾Hide ▴
Reasoning

The variant is a missense substitution and SpliceAI max delta is 0.011, below the VCEP's 0.1 no-splicing threshold; however, no previously classified pathogenic or likely pathogenic variant producing the same amino-acid change was found in the governing ENIGMA files. Searches for c.9257G>C, p.Gly3086Ala, p.G3086A, Gly3086, G3086, and residue 3086 found no same-residue comparator entry; the only relevant 3086 entries were exon-boundary/domain-table coordinates. The criterion therefore cannot be evaluated without a qualifying reference variant.

VCEP rule
Apply PS1, for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)). ... Apply PS1_Moderate, for predicted missense substitutions, where previously established likely pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).
Evidence considered
  • Case normalization identifies NM_000059.4:c.9257G>C as NP_000050.3:p.(Gly3086Ala), also p.(G3086A). SpliceAI max delta is 0.011.
  • The ENIGMA governing files were searched for c.9257G>C, p.Gly3086Ala, p.G3086A, Gly3086, G3086, and residue 3086; no same-amino-acid pathogenic comparator was found.
  • SupplementaryTables_V1.2_2024-11-18.xlsx.txt contains exon-coordinate rows ending/starting at amino-acid 3086, including BRCA2 exon 25 c.9257-9501, p.3086-3167, but no c.9257G>C or p.Gly3086Ala comparator row.
  • PMID:31143303 Table 2 explicitly lists BRCA2 c.9257G>C p.(Gly3086Ala) and reports it as splice class 1S with no observed splicing effect; this addresses the splicing prerequisite but does not establish the required prior pathogenic same-amino-acid comparator.
Still missing
  • No qualifying same-amino-acid pathogenic or likely pathogenic comparator was found in Specifications_V1.2_2024-11-18.docx.
  • No qualifying same-amino-acid pathogenic or likely pathogenic comparator was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No qualifying same-amino-acid pathogenic or likely pathogenic comparator was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No qualifying same-amino-acid pathogenic or likely pathogenic comparator was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗PMID:31143303 ↗
PS3 VCEPNot assessed: no qualifying calibrated protein-function result was found, while the available variant-specific assay was mRNA-only and showed no splicing abnormality. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 v1.2 PS3 rule requires well-established functional studies showing a damaging effect and specifies that PS3 applies when the assay measures protein alone or mRNA and protein together. The exact-variant searches found no row for c.9257G>C, p.Gly3086Ala, or p.G3086A in Specifications_Table9_V1.2_2024-11-18.xlsx, SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx. PMID:31143303 reports this variant in a patient-blood RNA assay as splice class 1S with no observed splicing effect, but ENIGMA Appendix E reserves PS3/BS3 for protein-function impact and routes mRNA-only evidence to alternative RNA codes; therefore this result does not establish PS3 and cannot be used to call PS3 not_met. No qualifying calibrated protein-function assay result was identified.

VCEP rule
Well-established in vitro or in vivo functional studies supportive of a damaging effect Assay measures effect via protein only OR mRNA and protein combined. See Appendix E See Figure 1C for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. See Table 9, provided as a separate excel spreadsheet, for a comprehensive table of applicable codes using published calibrated functional assay results.
Evidence considered
  • ENIGMA BRCA2 v1.2 Specifications, PS3 functional-assay rule: damaging functional studies qualify when the assay measures protein alone or mRNA and protein combined; mRNA-only assays use an alternative code.
  • ENIGMA BRCA2 v1.2 Appendix E: PS3 and BS3 are reserved for protein-function impact; splicing-assay evidence is recorded under PVS1 or BP7 rather than PS3/BS3.
  • ENIGMA Specifications Table 9, exact-variant search for c.9257G>C, p.Gly3086Ala, and p.G3086A: no matching row found.
  • SupplementaryTables_V1.2_2024-11-18.xlsx, exact-variant search for c.9257G>C, p.Gly3086Ala, and p.G3086A: no matching row found.
  • Specifications_V1.2_2024-11-18.docx, exact-variant search for c.9257G>C, p.Gly3086Ala, and p.G3086A: no matching row found.
  • Appendices_V1.2_2024-11-18.docx, exact-variant search for c.9257G>C, p.Gly3086Ala, and p.G3086A: no matching row found.
  • HUMU-40-1557-s001.xlsx, exact-variant search for c.9257G>C, p.Gly3086Ala, and p.G3086A: no matching row found.
  • Wangensteen et al. 2019, Table 2 and Discussion (PMID:31143303): c.9257G>C, p.(Gly3086Ala) was splice class 1S in a patient-blood RNA assay, with no observed splicing effect and biallelic expression; the assay did not assess protein function.
Still missing
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A row found in Specifications_Table9_V1.2_2024-11-18.xlsx.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A row found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A row found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A row found in Appendices_V1.2_2024-11-18.docx.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A row found in HUMU-40-1557-s001.xlsx.
  • A qualifying calibrated protein-function assay for p.Gly3086Ala was not available in the reviewed evidence.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_specifications_table9_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗PMID:31143303 ↗
PS4 VCEPNot assessed: no exact variant-level case-control p-value, OR, or confidence interval was available to test the ENIGMA PS4 thresholds. Details ▾Hide ▴
Reasoning

The governing ENIGMA rule requires a case-control study with p-value ≤0.05, OR ≥4, and a lower confidence interval excluding 2.0. No exact variant-level case-control result or pre-assigned PS4 code was found for c.9257G>C, p.Gly3086Ala, or p.G3086A in SupplementaryTables_V1.2_2024-11-18.xlsx, HUMU-40-1557-s001.xlsx, or the case evidence bundle; therefore PS4 cannot be evaluated without substituting non-VCEP evidence.

VCEP rule
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. ... Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0).
Evidence considered
  • ENIGMA Specifications V1.2, PS4 rule: case-control studies require p-value ≤0.05 and OR ≥4, with the lower confidence interval excluding 2.0.
  • SupplementaryTables_V1.2_2024-11-18.xlsx was searched for c.9257G>C, p.Gly3086Ala, and p.G3086A; no exact variant row was found.
  • HUMU-40-1557-s001.xlsx was searched for c.9257G>C, p.Gly3086Ala, and p.G3086A; no exact variant row was found.
Still missing
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx; the file was searched for all three notations.
  • No exact variant-level case-control p-value, odds ratio, or confidence interval was found in HUMU-40-1557-s001.xlsx or the case evidence bundle.
Sources
cspec ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗
PP1 VCEPNot assessed: no variant-specific pedigree or quantitative segregation likelihood ratio was available to compare with the VCEP's PP1 threshold of LR ≥2.08:1. Details ▾Hide ▴
Reasoning

Not assessed: the VCEP requires co-segregation with disease in multiple affected family members measured by a quantitative co-segregation method and assigns strength from a Bayes-score LR. The available case evidence contains no variant-specific pedigree, affected-relative genotypes, parental testing, meioses, or quantitative segregation LR for c.9257G>C/p.Gly3086Ala, so PP1 cannot be evaluated without substituting a non-VCEP rule.

VCEP rule
Co-segregation with disease in multiple affected family members ... See Appendix I for details. ... Apply weight as per Bayes Score: ... PP1 - LR ≥2.08:1 ... PP1_Moderate – LR≥4.3:1 ... PP1_Strong – LR≥18.7:1 ... PP1_Very Strong – LR≥350:1
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, PP1 entry: co-segregation with disease in multiple affected family members; Bayes-score thresholds are PP1 LR ≥2.08:1, PP1_Moderate LR ≥4.3:1, PP1_Strong LR ≥18.7:1, and PP1_Very Strong LR ≥350:1.
  • Appendices_V1.2_2024-11-18.docx, Appendix I: the preferred method is Bayesian quantitative co-segregation analysis, and the Bayes score directly measures evidence across available family evidence, including untested individuals and ascertainment due to proband cancer status.
  • The bundle's exact-variant literature extraction includes PMID:31143303, which reports an mRNA splicing assay for c.9257G>C/p.Gly3086Ala but provides no pedigree, parental testing, meioses, or segregation LR.
Still missing
  • The case-evidence bundle contains no variant-specific pedigree, affected-relative genotypes, parental testing, meioses, or quantitative segregation LR.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in HUMU-40-1557-s001.xlsx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗PMID:31143303 ↗
PP4 VCEPNot assessed: no exact combined clinical likelihood ratio was available to test the ENIGMA PP4 threshold of LR ≥2.08:1. Details ▾Hide ▴
Reasoning

The ENIGMA rule permits PP4 only for combined multifactorial clinical likelihood data and requires LR ≥2.08:1 for Supporting, ≥4.3:1 for Moderate, ≥18.7:1 for Strong, or ≥350:1 for Very Strong. The exact variant was not found in the Li et al. BRCA2 clinical-history LR table, and no exact combined clinical LR or pre-assigned PP4 code was found in the named VCEP tables; PP4 is therefore not assessed.

VCEP rule
Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data. ... PP4 - LR ≥2.08:1 ... PP4_Moderate – LR≥4.3:1 ... PP4_Strong – LR≥18.7:1 ... PP4_Very Strong – LR≥350:1
Evidence considered
  • ENIGMA Specifications V1.2, PP4 rule: breast cancer phenotype is not sufficiently specific by itself; use PP4 only for combined LR from multifactorial likelihood clinical data.
  • The governing PP4 thresholds are LR ≥2.08:1 for Supporting, LR ≥4.3:1 for Moderate, LR ≥18.7:1 for Strong, and LR ≥350:1 for Very Strong.
  • PMID_31853058_BRCA2_clinical_history_LR.xlsx was searched for c.9257G>C, p.Gly3086Ala, and p.G3086A; no exact variant row was found.
Still missing
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in PMID_31853058_BRCA2_clinical_history_LR.xlsx; the file was searched for all three notations.
  • No exact variant-level combined clinical LR or pre-assigned PP4 code was found in the VCEP files searched.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_pmid_31853058_brca2_clinical_history_lr ↗PMID:31853058 ↗
BS2 VCEPNot assessed: one gnomAD homozygote lacks the VCEP-required phenotyped-individual and age/follow-up data for BS2. Details ▾Hide ▴
Reasoning

BS2 is not assessed. The VCEP requires observations in healthy or phenotyped individuals and assigns points according to the individual's age at cancer diagnosis or age at last follow-up, inheritance/phase, and absence of Fanconi Anemia features. The available population data show one homozygote in gnomAD v2.1 non-cancer exomes, but the VCEP explicitly states that frequency-code data are not to be used for BS2 and that homozygote observations in gnomAD are captured by BA1 or BS1 only when the applicable frequency thresholds are met. No qualifying phenotyped individual, age/follow-up information, phase, or Fanconi Anemia assessment is available.

VCEP rule
Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details. BS2 = ≥ 4 points
Evidence considered
  • gnomAD v2.1 non-cancer exomes report one homozygote, but this is population-frequency data rather than a phenotyped healthy-adult observation.
  • The ENIGMA BRCA2 specification Table 8 assigns BS2 points using age at first cancer or age at last follow-up, inheritance/phase, and the absence of Fanconi Anemia features.
  • The ENIGMA BRCA2 specification states that gnomAD frequency data are not to be used for BS2 point assignment.
Still missing
  • No qualifying healthy adult or phenotyped cohort observation with age at last follow-up, cancer age, phase, and Fanconi Anemia assessment is available.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗
BS3 VCEPNot assessed: the only variant-specific assay was mRNA-only, showing no splicing abnormality but providing no calibrated evidence that the encoded protein is functionally benign. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 v1.2 BS3 rule requires well-established functional studies showing no damaging effect on protein function and specifies protein-only or combined mRNA-and-protein assays. The exact-variant searches found no row for c.9257G>C, p.Gly3086Ala, or p.G3086A in Specifications_Table9_V1.2_2024-11-18.xlsx, SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx. PMID:31143303 found no splicing abnormality for the variant in an mRNA-only assay, but this does not establish absence of damaging protein impact; ENIGMA Appendix E excludes mRNA-only splicing evidence from BS3. Therefore BS3 is not assessed rather than met or not_met.

VCEP rule
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details. Well-established _in vitro_ or _in vivo_ functional studies supportive of no damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.
Evidence considered
  • ENIGMA BRCA2 v1.2 Specifications, BS3 functional-assay rule: no-damaging-effect studies qualify when the assay measures protein alone or mRNA and protein combined; mRNA-only assays use BP7 (RNA).
  • ENIGMA BRCA2 v1.2 Appendix E: PS3 and BS3 are reserved for protein-function impact; splicing-assay evidence is recorded under PVS1 or BP7 rather than PS3/BS3.
  • ENIGMA Specifications Table 9, exact-variant search for c.9257G>C, p.Gly3086Ala, and p.G3086A: no matching row found.
  • SupplementaryTables_V1.2_2024-11-18.xlsx, exact-variant search for c.9257G>C, p.Gly3086Ala, and p.G3086A: no matching row found.
  • Specifications_V1.2_2024-11-18.docx, exact-variant search for c.9257G>C, p.Gly3086Ala, and p.G3086A: no matching row found.
  • Appendices_V1.2_2024-11-18.docx, exact-variant search for c.9257G>C, p.Gly3086Ala, and p.G3086A: no matching row found.
  • HUMU-40-1557-s001.xlsx, exact-variant search for c.9257G>C, p.Gly3086Ala, and p.G3086A: no matching row found.
  • Wangensteen et al. 2019, Table 2 and Discussion (PMID:31143303): c.9257G>C, p.(Gly3086Ala) was splice class 1S in a patient-blood RNA assay, with no observed splicing effect and biallelic expression; the assay did not assess protein function.
Still missing
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A row found in Specifications_Table9_V1.2_2024-11-18.xlsx.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A row found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A row found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A row found in Appendices_V1.2_2024-11-18.docx.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A row found in HUMU-40-1557-s001.xlsx.
  • A qualifying calibrated protein-function assay demonstrating no damaging effect for p.Gly3086Ala was not available in the reviewed evidence.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_specifications_table9_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗PMID:31143303 ↗
BS4 VCEPNot assessed: no variant-specific pedigree or quantitative negative-segregation likelihood ratio was available to compare with the VCEP's BS4 threshold of LR ≤0.48:1. Details ▾Hide ▴
Reasoning

Not assessed: the VCEP requires lack of segregation in affected family members measured by a quantitative co-segregation method and assigns strength from a Bayes-score LR. The available case evidence contains no variant-specific pedigree, affected-relative genotypes, parental testing, meioses, or quantitative negative-segregation LR for c.9257G>C/p.Gly3086Ala, so BS4 cannot be evaluated without substituting a non-VCEP rule.

VCEP rule
Lack of segregation in affected members of a family. ... See Appendix I. ... Apply weight as per Bayes Score: ... BS4_Supporting - LR ≤0.48 to >0.23:1 ... BS4_Moderate - LR ≤0.23:1 ... BS4 - LR ≤0.05:1 ... BS4_Very strong – LR ≤0.00285:1
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, BS4 entry: lack of segregation in affected members of a family; Bayes-score thresholds are BS4 Supporting LR ≤0.48:1, BS4 Moderate LR ≤0.23:1, BS4 LR ≤0.05:1, and BS4 Very strong LR ≤0.00285:1.
  • Appendices_V1.2_2024-11-18.docx, Appendix I: the preferred method is Bayesian quantitative co-segregation analysis, with Bayes scores converted to PP1 or BS4 strength categories.
  • The bundle's exact-variant literature extraction includes PMID:31143303, which reports an mRNA splicing assay for c.9257G>C/p.Gly3086Ala but provides no pedigree, parental testing, meioses, or segregation LR.
Still missing
  • The case-evidence bundle contains no variant-specific pedigree, affected-relative genotypes, parental testing, meioses, or quantitative negative-segregation LR.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in HUMU-40-1557-s001.xlsx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗PMID:31143303 ↗
BP5 VCEPNot assessed: no exact combined clinical LR was available to test the ENIGMA BP5 operator LR ≤0.48:1. Details ▾Hide ▴
Reasoning

The ENIGMA rule permits BP5 only for combined multifactorial clinical likelihood data against pathogenicity. Its criterion-specific operators are LR ≤0.48 to >0.23:1 for Supporting, LR ≤0.23:1 for Moderate, LR ≤0.05:1 for Strong, and LR ≤0.00285:1 for Very Strong. No exact variant-level combined LR or pre-assigned BP5 code was found; therefore no inequality can be evaluated.

VCEP rule
Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data. ... BP5_VeryStrong – LR ≤0.00285:1 ... BP5_Strong - LR ≤0.05:1 ... BP5_Moderate - LR ≤0.23:1 ... BP5 - LR ≤0.48 to >0.23:1
Evidence considered
  • ENIGMA Specifications V1.2, BP5 rule: use only combined LR against pathogenicity from multifactorial likelihood clinical data.
  • The criterion-specific BP5 operators are LR ≤0.00285:1 for Very Strong, LR ≤0.05:1 for Strong, LR ≤0.23:1 for Moderate, and LR ≤0.48 to >0.23:1 for Supporting.
  • PMID_31853058_BRCA2_clinical_history_LR.xlsx was searched for c.9257G>C, p.Gly3086Ala, and p.G3086A; no exact variant row was found.
Still missing
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in PMID_31853058_BRCA2_clinical_history_LR.xlsx; the file was searched for all three notations.
  • No exact variant-level combined clinical LR or pre-assigned BP5 code was found in the VCEP files searched.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_pmid_31853058_brca2_clinical_history_lr ↗PMID:31853058 ↗
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.9257G>C is a missense p.Gly3086Ala substitution, whereas ENIGMA PVS1 applies to specified null variants. Details ▾Hide ▴
Reasoning

NM_000059.4:c.9257G>C is an exonic missense variant, NP_000050.3:p.(Gly3086Ala), in exon 25, not a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-deletion null variant. The ENIGMA BRCA2 PVS1 rule is limited to null variants, and the exact variant was not found 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. An exact-variant mRNA study reported normal splicing, but this does not convert the missense consequence into a PVS1-eligible null consequence.

VCEP rule
Null variant in a gene where loss of function is a known mechanism of disease. ... Apply according to PVS1 flowchart, which considers knowledge of clinically important functional domains. For predicted protein termination codon (PTC) variants, apply with exon-specific weights derived for the PM5 (PTC) code (see description below).
Evidence considered
  • Case normalization: NM_000059.4:c.9257G>C; NP_000050.3:p.(Gly3086Ala), p.(G3086A); exon 25; consequence class missense.
  • ENIGMA Specifications Table 1, PVS1_VariableWeight: the governing variant category is a null variant; Table 4 covers initiation, nonsense/frameshift, deletion, duplication, and canonical splice-site PVS1 decisions.
  • Specifications Table 4, BRCA2 exon 25 row: the exon-level entries concern PTC, exon deletion/duplication, and canonical splice-site variants; the exact missense variant is not listed.
  • Wangensteen et al. 2019 mRNA assay, Table 2 and Discussion: BRCA2 c.9257G>C p.(Gly3086Ala) was splice class 1S with no observed splicing effect; the assay used patient blood RNA, RT-PCR, fragment analysis, sequencing, and biallelic-expression assessment.
Still missing
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗PMID:31143303 ↗
PS2 VCEPNot applicable: the VCEP explicitly says to not use PS2 because de novo occurrences lack calibrated predictive information for BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

Not applicable: the ENIGMA BRCA2 specification states that PS2 is not to be used because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.

VCEP rule
De novo (paternity confirmed) in a patient with the disease and no family history. ... Do not use ... BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, PS2 entry: "De novo (paternity confirmed) in a patient with the disease and no family history." followed by "Do not use" and the stated lack of calibration for de novo occurrences.
Still missing
  • No de novo evidence was available in the case-evidence bundle; this does not change the VCEP's explicit instruction not to use PS2.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx.
Sources
cspec ↗
PM1 VCEPNot applicable: the ENIGMA specification says PM1 is not to be used, even though residue 3086 lies in the DNA-binding region. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly states that PM1 is not to be used and is considered a component of bioinformatic analysis (PP3/BP4). The authoritative vcep_materials.json domain_tables key is empty. Although residue 3086 lies within the text-defined BRCA2 DNA-binding region, that domain location does not activate PM1 under this VCEP.

VCEP rule
Located in a mutational hot spot and/or critical and well-established functional domain. ... Do not use ... Considered as component of bioinformatic analysis (PP3/BP4).
Evidence considered
  • Specifications_V1.2_2024-11-18.docx states under PM1: Located in a mutational hot spot and/or critical and well-established functional domain; Do not use; Considered as component of bioinformatic analysis (PP3/BP4).
  • The structured VCEP materials contain domain_tables: {}, so no gene-specific extracted domain table entry supersedes the governing PM1 prohibition.
  • The VCEP text defines the BRCA2 DNA-binding domain as aa 2481-3186; residue 3086 is within that interval, but this does not change PM1's not-to-be-used status.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
PM4 VCEPNot applicable: PM4 is explicitly not used by ENIGMA, and p.Gly3086Ala is a missense substitution without a protein-length change. Details ▾Hide ▴
Reasoning

PM4 is explicitly marked Do not use by the ENIGMA BRCA2 specification and is described only for protein-length changes from in-frame deletions/insertions in a non-repeat region or stop-loss variants. This variant is a missense substitution, p.(Gly3086Ala), with no protein-length change.

VCEP rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. ... Do not use ... Considered as component of bioinformatic analysis (PP3/BP4).
Evidence considered
  • ENIGMA Specifications Table 1, PM4 row: protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants; Do not use; considered as a component of PP3/BP4.
  • Case normalization identifies p.(Gly3086Ala), a missense substitution, so there is no in-frame insertion/deletion or stop-loss protein-length change.
Still missing
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PM5 N/ANot applicable: PM5 is not used for missense variants under ENIGMA and the variant is not a protein-termination-codon change. Details ▾Hide ▴
Reasoning

The VCEP explicitly says the missense PM5 code is not to be used and repurposes PM5 only as PM5_VariableWeight (PTC) for protein termination codon variants annotated as PVS1. This variant is missense, not a PTC variant.

VCEP rule
Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Do not use ... Considered as component of bioinformatic analysis (PP3/BP4). ... 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.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx states for PM5 missense change: Do not use; Considered as component of bioinformatic analysis (PP3/BP4).
  • The same specification defines PM5_VariableWeight (PTC) for a protein termination codon variant in an exon where a different proven pathogenic PTC variant has been seen before, applied as additional weight for PVS1; c.9257G>C is a missense variant producing p.Gly3086Ala.
  • Specifications_Table4_V1.2_2024-11-18.xlsx.txt and SupplementaryTables_V1.2_2024-11-18.xlsx.txt were searched; their relevant 3086 rows concern exon/PTC coordinates, not this missense PM5 path.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗
PM6 VCEPNot applicable: the VCEP explicitly says to not use PM6 because de novo occurrences lack calibrated predictive information for BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

Not applicable: the ENIGMA BRCA2 specification states that PM6 is not to be used because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.

VCEP rule
Confirmed de novo without confirmation of paternity and maternity. ... Do not use ... BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, PM6 entry: "Confirmed de novo without confirmation of paternity and maternity." followed by "Do not use" and the stated lack of calibration for de novo occurrences.
Still missing
  • No de novo evidence was available in the case-evidence bundle; this does not change the VCEP's explicit instruction not to use PM6.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx.
Sources
cspec ↗
PP2 VCEPNot applicable: ENIGMA says PP2 is not to be used because BRCA2 has a high frequency of benign missense variants. Details ▾Hide ▴
Reasoning

The ENIGMA specification explicitly marks PP2 as not to be used because BRCA2 has a high frequency of benign missense variants.

VCEP rule
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. ... Do not use ... High frequency of benign missense variants.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx states under PP2: Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease; Do not use; High frequency of benign missense variants.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PP5 VCEPNot applicable: the ENIGMA BRCA2 specification explicitly says PP5 should not be used. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly states that PP5 is not to be used. No PP5 assertion is made.

VCEP rule
Reputable source recently reports variant as pathogenic but the evidence is not available to the laboratory to perform an independent evaluation. ... Do not use
Evidence considered
  • ENIGMA Specifications V1.2, PP5 entry: reputable-source reports are not used for PP5 because the evidence is not independently evaluable.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP1 N/ANot applicable: residue 3086 is inside the ENIGMA DNA-binding domain aa 2481-3186, whereas BP1 requires a variant outside that domain. Details ▾Hide ▴
Reasoning

BP1 requires a missense variant outside a potentially clinically important functional domain and no predicted splicing. The variant is at residue 3086, within the VCEP-defined BRCA2 DNA-binding domain aa 2481-3186, so the location requirement for BP1 is not met.

VCEP 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).
Evidence considered
  • The VCEP BP1 rule requires silent, missense, or in-frame variants outside a potentially clinically important functional domain and no splicing predicted (SpliceAI <=0.1).
  • The VCEP defines the BRCA2 DNA-binding domain as aa 2481-3186; residue 3086 is inside that domain.
  • Case SpliceAI max delta is 0.011, satisfying the no-splicing component, but the required outside-domain component is absent.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
BP2 VCEPNot applicable: the VCEP explicitly says BP2 is not used and permits it only in the context of BS2. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP explicitly marks BP2 as not applicable and states that it is not used, with any related application restricted to BS2. Therefore, phase or co-occurrence observations cannot establish BP2 under this governing specification.

VCEP rule
Do not use Applied only in the context of BS2.
Evidence considered
  • ENIGMA BRCA2 specification v1.2, Table 1/BP2: the criterion is marked not applicable; the specification states 'Do not use' and 'Applied only in the context of BS2.'
Sources
cspec ↗
BP3 VCEPNot applicable: BP3 is explicitly not used by ENIGMA, and p.Gly3086Ala is not an in-frame deletion or insertion in a repeat region. Details ▾Hide ▴
Reasoning

BP3 is explicitly marked Do not use by the ENIGMA BRCA2 specification and is limited to in-frame deletions/insertions in a repetitive region without a known function. This variant is a missense substitution, p.(Gly3086Ala), not an in-frame deletion or insertion.

VCEP rule
In-frame deletions/insertions in a repetitive region without a known function. ... Do not use ... Captured by bioinformatic tool prediction, and domain analysis. See Appendix J.
Evidence considered
  • ENIGMA Specifications Table 1, BP3 row: in-frame deletions/insertions in a repetitive region without a known function; Do not use; captured by bioinformatic tool prediction and domain analysis.
  • Case normalization identifies p.(Gly3086Ala), a missense substitution rather than an in-frame deletion or insertion.
Still missing
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP6 VCEPNot applicable: the ENIGMA BRCA2 specification explicitly says BP6 should not be used. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly states that BP6 is not to be used. No BP6 assertion is made.

VCEP rule
Reputable source recently reports variant as benign but the evidence is not available to the laboratory to perform an independent evaluation. ... Do not use
Evidence considered
  • ENIGMA Specifications V1.2, BP6 entry: reputable-source reports are not used for BP6 because the evidence is not independently evaluable.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP7 N/ANot applicable: BP7 covers silent or qualifying intronic variants, or missense variants outside domains, whereas p.Gly3086Ala is missense inside the DNA-binding domain. Details ▾Hide ▴
Reasoning

BP7 is limited by the ENIGMA rule to silent variants inside a clinically important domain or intronic variants outside conserved donor or acceptor motif positions, and its RNA repurposing pathway applies to intronic, silent, and missense/in-frame variants outside a clinically important domain. This variant is missense and lies inside the BRCA2 DNA-binding domain (aa 2481-3186), so BP7 is outside its own scope. The no-splice result is therefore not used to assign BP7.

VCEP rule
Apply BP7 for ... Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. ... Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met ... Apply as BP7_Strong (RNA) for intronic, silent, and missense/in-frame variants located outside a (potentially) clinically important functional domain.
Evidence considered
  • The VCEP BP7 scope is silent variants inside a clinically important domain if BP4 is met, intronic variants at or beyond +7/-21 if BP4 is met, and BP7_Strong(RNA) for intronic, silent, and missense/in-frame variants outside a clinically important domain.
  • The case variant is missense p.Gly3086Ala at residue 3086, inside the VCEP-defined BRCA2 DNA-binding domain aa 2481-3186; it is neither silent nor intronic and is not outside the domain.
Still missing
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗

Identifiers

Gene
BRCA2
Transcript
NM_000059.4
Coding (HGVS c.)
NM_000059.4:c.9257G>C
Protein (HGVS p.)
NP_000050.3:p.(Gly3086Ala)
GRCh38
chr13:32394689 G>C
GRCh37
chr13:32968826 G>C
Location and type
Exon 25 · missense
ClinVar
156179

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 48 / 1,612,568 alleles AF 2.98e-05 · 1 homozygotes · FAF 0.000409
gnomAD v2.1 20 / 249,820 alleles AF 8.01e-05 · 1 homozygotes · FAF 0.000435
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 3e-05 · 48 / 1,612,568 alleles · 1 hom · FAF 0.00041
South Asian48 / 90,868 0.000531 hom
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).

gnomAD v2.1

AF 8e-05 · 20 / 249,820 alleles · 1 hom · FAF 0.00043
South Asian20 / 30,448 0.000661 hom
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.97662e-05; MAF= 0.00298%, 48/1612568 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000528239; MAF= 0.05282%, 48/90868 alleles, homozygotes = 1); grpmax FAF= 0.00040896.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 8.00576e-05; MAF= 0.00801%, 20/249820 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000656858; MAF= 0.06569%, 20/30448 alleles, homozygotes = 1); grpmax FAF= 0.00043457.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +0 bp
0.003
SpliceAI acceptor gainat +27 bp
0.011
SpliceAI donor lossat -331 bp
0.003
SpliceAI donor gainat +27 bp
0.000
Pangolin splice lossmagnitude shown
-0.027
Pangolin splice gain
0.010

Other predictors

REVEL
0.619
BayesDel
-0.029

How the predictions were used

BP4 SupportingVCEPMet, Supporting: BayesDel -0.0288497 is <=0.18 and SpliceAI 0.011 is <=0.1, satisfying both BRCA2 BP4 no-impact requirements. Details ▾Hide ▴
Reasoning

The variant is a missense substitution inside the BRCA2 DNA-binding domain (aa 2481-3186), so BP4 requires both no predicted protein impact and no predicted splice impact. BayesDel no-AF is -0.0288497, which is at or below the VCEP BRCA2 no-impact cutoff of 0.18, and SpliceAI maximum delta is 0.011, which is at or below 0.1. Both required components are met, so BP4 is met at Supporting strength. The exact variant was not found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

VCEP rule
Apply BP4 for: ... Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel predicted No Impact AND SpliceAI ≤0.1). ... BRCA2: No impact ≤ 0.18
Evidence considered
  • The ENIGMA VCEP defines BP4 for missense variants inside a clinically important functional domain only when BayesDel predicts no impact and SpliceAI is <=0.1; BRCA2 no-impact BayesDel cutoff is 0.18.
  • BayesDel no-AF score for NM_000059.4:c.9257G>C is -0.0288497, meeting the VCEP BRCA2 no-impact cutoff of <=0.18.
  • SpliceAI maximum delta score is 0.011, meeting the VCEP no-predicted-splicing cutoff of <=0.1.
  • Wangensteen et al. 2019 mRNA assay explicitly lists BRCA2 c.9257G > C p.(Gly3086Ala) in Table 2 and classifies it as splice class 1S with no observed splicing effect; this is concordant supporting context, not a replacement for the governing SpliceAI rule.
Still missing
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗bayesdelspliceai ↗PMID:31143303 ↗
PP3 VCEPNot met: BayesDel -0.0288497 is below the 0.30 PP3 threshold and SpliceAI 0.011 is below the 0.2 splice threshold. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, and p.Gly3086Ala lies within the BRCA2 DNA-binding domain (aa 2481-3186), so the VCEP PP3 protein-impact pathway is in scope. BayesDel no-AF is -0.0288497, below the BRCA2 PP3 impact threshold of 0.30. The independent VCEP splicing pathway is also not met: the SpliceAI maximum delta score is 0.011, below the PP3 threshold of 0.2. Therefore PP3 is not met; the same SpliceAI result is not counted again for BP4. The exact variant was not found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

VCEP rule
Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel predicted Impact). ... Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor ±1,2 positions.
Evidence considered
  • The case normalization identifies NM_000059.4:c.9257G>C as NP_000050.3:p.(Gly3086Ala), a missense variant at amino acid 3086; the ENIGMA BRCA2 DNA-binding domain is aa 2481-3186.
  • BayesDel no-AF score for the exact variant is -0.0288497. The VCEP Appendix J BRCA2 PP3 impact threshold is BayesDel >=0.30; this score does not meet it.
  • SpliceAI scores for NM_000059.4:c.9257G>C are DS_AG 0.011, DS_AL 0.003, DS_DG 0.0, and DS_DL 0.003; maximum delta score is 0.011. The VCEP PP3 splicing threshold is SpliceAI >=0.2; this result does not meet it.
  • The VCEP-governing files were searched for c.9257G>C, p.Gly3086Ala, and p.G3086A; no exact variant-level pre-assigned PP3 code was found.
Still missing
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗bayesdelspliceai ↗
BP7 N/ANot applicable: BP7 covers silent or qualifying intronic variants, or missense variants outside domains, whereas p.Gly3086Ala is missense inside the DNA-binding domain. Details ▾Hide ▴
Reasoning

BP7 is limited by the ENIGMA rule to silent variants inside a clinically important domain or intronic variants outside conserved donor or acceptor motif positions, and its RNA repurposing pathway applies to intronic, silent, and missense/in-frame variants outside a clinically important domain. This variant is missense and lies inside the BRCA2 DNA-binding domain (aa 2481-3186), so BP7 is outside its own scope. The no-splice result is therefore not used to assign BP7.

VCEP rule
Apply BP7 for ... Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. ... Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met ... Apply as BP7_Strong (RNA) for intronic, silent, and missense/in-frame variants located outside a (potentially) clinically important functional domain.
Evidence considered
  • The VCEP BP7 scope is silent variants inside a clinically important domain if BP4 is met, intronic variants at or beyond +7/-21 if BP4 is met, and BP7_Strong(RNA) for intronic, silent, and missense/in-frame variants outside a clinically important domain.
  • The case variant is missense p.Gly3086Ala at residue 3086, inside the VCEP-defined BRCA2 DNA-binding domain aa 2481-3186; it is neither silent nor intronic and is not outside the domain.
Still missing
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9257G>C, p.Gly3086Ala, or p.G3086A entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.619. BayesDel score = -0.0288497.

8 paper records listed. 1 cited in the classification.

Cited in the classification

  • Diagnostic mRNA splicing assay for variants in BRCA1 and BRCA2 identified two novel pathogenic splicing aberrations.
    Wangensteen T et al. · 2019
    The paper explicitly reports BRCA2 c.9257G>C, p.(Gly3086Ala) as an exonic amino-acid substitution analyzed by an mRNA splicing assay. It was classified as splice class 1S, indicating no observed effect on splicing with both alleles identified using informative SNPs; the authors state that protein-function impact requires separate assessment.
    → BP4 · supporting Names this variant
    PMID 31143303 ↗
    Source detail
    BRCA2 c.9257G > C p.(Gly3086Ala)

    Location Table 2; Discussion, paragraph beginning ‘Sixteen variants showed normal splicing.’

    Context Patient blood RNA mRNA splicing assay using reverse transcription-PCR, fragment analysis, sequencing, and assessment of biallelic expression; variant reported as splice class 1S.

Other recorded publications

  • Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay.
    Hu C et al. · 2022
    No paper-specific finding is recorded.
    PMID 35736817 ↗
  • Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
    No paper-specific finding is recorded.
    PMID 23918944 ↗
  • 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.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • Functional analysis and clinical classification of 462 germline BRCA2 missense variants affecting the DNA binding domain.
    Hu C et al. · 2024
    No paper-specific finding is recorded.
    PMID 38417439 ↗
  • The emerging landscape of breast cancer susceptibility.
    No paper-specific finding is recorded.
    PMID 18163131 ↗
  • American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
    No paper-specific finding is recorded.
    PMID 24493721 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

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

gnomAD v4.1 48 / 1,612,568 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.011 Open source ↗
ClinVar 6 Uncertain significance · 4 Likely benign · 2 Benign · 1 Uncertain Significance 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

This variant is present in gnomAD v4.1 (AF= 2.97662e-05; MAF= 0.00298%, 48/1612568 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000528239; MAF= 0.05282%, 48/90868 alleles, homozygotes = 1); grpmax FAF= 0.00040896.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 8.00576e-05; MAF= 0.00801%, 20/249820 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000656858; MAF= 0.06569%, 20/30448 alleles, homozygotes = 1); grpmax FAF= 0.00043457.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Benign (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 156179)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.619. BayesDel score = -0.0288497.

Functional

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

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.