Is BRCA2 p.Val2687Ala (c.8060T>C) pathogenic?

BRCA2 p.Val2687Ala (c.8060T>C) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-03). AlphaMissense: likely pathogenic (0.6075); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Val2687Ala (c.8060T>C)?

BRCA2 p.Val2687Ala (c.8060T>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.Val2687Ala (c.8060T>C) in the general population?

BRCA2 p.Val2687Ala (c.8060T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BRCA2 p.Val2687Ala (c.8060T>C)?

AlphaMissense predicts likely pathogenic (score 0.6075) — an in-silico prediction, not a clinical call.

BRCA2 p.Val2687Ala

c.8060T>C · rs374625452 · VCV230057

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.6075	likely pathogenic · top 6% in BRCA2
REVEL	0.833	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 2.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,880 alleles

Overall 0.000124% 2/1,614,142 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,880
African / African-American	0.00133%	75,054

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.Val2687Ala
Coding: c.8060T>C
MANE Select: NM_000059
dbSNP: rs374625452
Type: single nucleotide variant
Location: chr13:32363262 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2687: the 'interaction with sem1' region

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome

Similar variants

BRCA2 p.Val2687Phe Uncertain significance ★★★ ⚠ same residue
BRCA2 p.Val2687= Likely benign ★★★ same residue
BRCA2 p.Val2687Ile Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Val2687_Leu2688del Likely 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-val2687ala (accessed [today's date]).

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