The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_000059.4(BRCA2):c.9364G>C (p.Ala3122Pro)

CA387761167

439019 (ClinVar)

Gene: BRCA2 (HGNC:675)
Condition: BRCA2-related cancer predisposition (MONDO:0700269)
Inheritance Mode: Autosomal dominant inheritance
UUID: aafb9cc9-786a-4252-81fe-768288673f09
Approved on: 2025-12-03
Published on: 2025-12-02

HGVS expressions

NM_000059.4(BRCA2):c.9364G>C (p.Ala3122Pro)
NM_000059.4:c.9364G>C
NC_000013.11:g.32394796G>C
CM000675.2:g.32394796G>C
NC_000013.10:g.32968933G>C
CM000675.1:g.32968933G>C
NC_000013.9:g.31866933G>C
NG_012772.3:g.84317G>C
ENST00000470094.2:c.9364G>C
ENST00000528762.2:c.*731G>C
ENST00000530893.7:c.8995G>C
ENST00000665585.2:c.*926G>C
ENST00000666593.2:c.*209G>C
ENST00000700202.2:c.9313G>C
ENST00000700202.1:c.1780G>C
ENST00000700203.1:n.1491G>C
ENST00000380152.8:c.9364G>C
ENST00000544455.6:c.9364G>C
ENST00000614259.2:c.9372G>C
ENST00000665585.1:c.2242G>C
ENST00000666593.1:c.386G>C
ENST00000680887.1:c.9364G>C
ENST00000380152.7:c.9364G>C
ENST00000470094.1:c.321G>C
ENST00000544455.5:c.9364G>C
NM_000059.3:c.9364G>C
More

Likely Pathogenic

Met criteria codes 3
PM2_Supporting PS3 PP1_Moderate
Not Met criteria codes 3
BP4 BP1 PP3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.2.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
ENIGMA BRCA1 and BRCA2 VCEP
The c.9364G>C variant in BRCA2 is a missense variant predicted to cause substitution of alanine by proline at amino acid 3122 (p.Ala3122Pro). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.22, indicating impact on BRCA2 function via protein change is unclear (score range 0.18-0.30). A SpliceAI score of 0.00 predicts no impact on splicing (score threshold ≤0.1) (no bioinformatic code is applied). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 39779857, 39779848) (PS3 met). Cosegregation analysis of two families carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 16.96 (applied as LR), within the thresholds for moderate pathogenic evidence (LR ≥4.3 & <18.7) (PP1_Moderate met; Internal lab contributors). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP1_Moderate).
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met).
PS3
Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 39779857, 39779848) (PS3 met).
PP1_Moderate
Cosegregation analysis of two families carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 16.96 (applied as LR), within the thresholds for moderate pathogenic evidence (LR ≥4.3 & <18.7) (PP1_Moderate met; Internal lab contributors).
Not Met criteria codes
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.22, indicating impact on BRCA2 function via protein change is unclear (score range 0.18-0.30). A SpliceAI score of 0.00 predicts no impact on splicing (score threshold ≤0.1) (no bioinformatic code is applied).
Curation History
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