Variant: NM_000059.4(BRCA2):c.7967T>A (p.Leu2656Gln)

Version: 1.0
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CA16613950

409564 (ClinVar)

Gene: BRCA2 (HGNC:675)

Condition: BRCA2-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: dba4db7d-bf0b-4f56-978a-4c3187cfdf29

Approved on: 2025-12-03

Published on: 2025-12-02

HGVS expressions

NM_000059.4:c.7967T>A
NM_000059.4(BRCA2):c.7967T>A (p.Leu2656Gln)
NC_000013.11:g.32362684T>A
CM000675.2:g.32362684T>A
NC_000013.10:g.32936821T>A
CM000675.1:g.32936821T>A
NC_000013.9:g.31834821T>A
NG_012772.3:g.52205T>A
ENST00000470094.2:c.7967T>A
ENST00000528762.2:c.7967T>A
ENST00000530893.7:c.7598T>A
ENST00000665585.2:c.7967T>A
ENST00000666593.2:c.7967T>A
ENST00000700202.2:c.7967T>A
ENST00000700202.1:c.434T>A
ENST00000380152.8:c.7967T>A
ENST00000544455.6:c.7967T>A
ENST00000614259.2:c.7975T>A
ENST00000665585.1:c.532T>A
ENST00000680887.1:c.7967T>A
ENST00000380152.7:c.7967T>A
ENST00000544455.5:c.7967T>A
NM_000059.3:c.7967T>A

Likely Pathogenic

• Met criteria codes: PP3 PS3 PM2_Supporting

Expert Panel

ENIGMA BRCA1 and BRCA2 VCEP

Criteria Specification Information

Criteria Specification: ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.1.0

Evidence submitted by expert panel

ENIGMA BRCA1 and BRCA2 VCEP

The c.7967T>A variant in BRCA2 is a missense variant predicted to cause substitution of Leucine by Glutamine at amino acid 2656 (p.(Leu2656Gln)). 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). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 38417439, 39779857, 39779848) (PS3 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.416, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0.03 predicts no impact on splicing (score threshold ≤0.1) (PP3 met). 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, PP3).

Met criteria codes

• PP3: This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.416, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0.03 predicts no impact on splicing (score threshold ≤0.1) (PP3 met).
• PS3: Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 38417439, 39779857, 39779848) (PS3 met).
• 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).