Is BRCA2 p.Leu2656Gln (c.7967T>A) pathogenic?

BRCA2 p.Leu2656Gln (c.7967T>A) is classified Likely pathogenic in BRCA2 (ClinVar, Expert panel, 4 submitters; last evaluated 2025-12-02). AlphaMissense: likely pathogenic (0.9678); Absent from gnomAD v4.1; Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Leu2656Gln (c.7967T>A)?

BRCA2 p.Leu2656Gln (c.7967T>A) is associated with BRCA2-related cancer predisposition, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Leu2656Gln (c.7967T>A) in the general population?

BRCA2 p.Leu2656Gln (c.7967T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA2 p.Leu2656Gln (c.7967T>A)?

AlphaMissense predicts likely pathogenic (score 0.9678) — an in-silico prediction, not a clinical call.

BRCA2 p.Leu2656Gln

c.7967T>A · rs886037817 · VCV409564

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9678 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

BRCA2-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.9678	likely pathogenic ✓ concordant with ClinVar · top 1% in BRCA2
REVEL	0.896	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP

Likely Pathogenic for BRCA2-related cancer predisposition. Applied ACMG criteria (verbatim):

PM2_Supporting PS3 PP3

Curation rationale (ClinGen, verbatim)

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).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Variant & gene context

Gene: BRCA2
Protein: p.Leu2656Gln
Coding: c.7967T>A
MANE Select: NM_000059
dbSNP: rs886037817
Type: single nucleotide variant
Location: chr13:32362684 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2656: the 'interaction with sem1' region

Full BRCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: hereditary breast ovarian cancer syndrome hereditary neoplastic syndrome

Similar variants

BRCA2 p.Leu2656= Likely benign ★★ same residue
BRCA2 p.Leu2656Val Uncertain significance ★ ⚠ same residue
BRCA2 p.Leu2656Pro Uncertain significance ★ ⚠ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>C Pathogenic ★★★ same condition
BRCA2 c.316+5G>A Pathogenic ★★★ same condition
BRCA2 c.316+5G>C Pathogenic ★★★ same condition
BRCA2 c.475+1G>A Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/brca2-p-leu2656gln (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown