BRCA2 p.Val2652Gly
c.7955T>G · rs1555286868 · VCV489784
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.7955T>G variant in BRCA2 is a missense variant predicted to cause substitution of Valine by Glycine at amino acid 2652 (p.(Val2652Gly)). 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 five calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 32444794, 35190686, 39779857, 39779848) (PS3 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.42, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0.01 predicts no impact on splicing (score threshold <0.10) (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.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.7357 | likely pathogenic ✓ concordant with ClinVar · top 4% 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 6.1 | GERP 2.5, phastCons 1 |
| Regional constraint | o/e 1.03 | unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic |
| Overall | ||
| CADD | 25.5 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- BRCA2
- Protein
- p.Val2652Gly
- Coding
- c.7955T>G
- MANE Select
- NM_000059
- dbSNP
- rs1555286868
- Type
- single nucleotide variant
- Location
- chr13:32362672 (GRCh38)
- Gene constraint
- LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Residue 2652
- the 'interaction with sem1' region
Similar variants
- BRCA2 p.Val2652Met Uncertain significance ★★ ⚠ same residue
- BRCA2 p.Val2652= Conflicting classifications of pathogenicity ★ same residue
- BRCA2 p.Val2652Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
- BRCA2 p.Val2652fs Pathogenic ★★★ 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
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-val2652gly (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown