Is BRCA2 p.Val2687Phe (c.8059G>T) pathogenic?

BRCA2 p.Val2687Phe (c.8059G>T) is classified Uncertain significance in BRCA2 (ClinVar, Expert panel, 6 submitters; last evaluated 2025-08-18). AlphaMissense: likely pathogenic (0.6901); Very rare (popmax 0.0011%, sas); Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Val2687Phe (c.8059G>T)?

BRCA2 p.Val2687Phe (c.8059G>T) is associated with BRCA2-related cancer predisposition, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Val2687Phe (c.8059G>T) in the general population?

BRCA2 p.Val2687Phe (c.8059G>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about BRCA2 p.Val2687Phe (c.8059G>T)?

AlphaMissense predicts likely pathogenic (score 0.6901) — an in-silico prediction, not a clinical call.

BRCA2 p.Val2687Phe

c.8059G>T · rs80359044 · VCV52491

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6901 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

BRCA2-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.6901	likely pathogenic · top 5% in BRCA2
REVEL	0.811	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 1.9	GERP 0.39, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	23.1	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 0.0011% South Asian · 1/91,082 alleles

Overall 6.84e-05% 1/1,461,808 alleles · very rare

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.

ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP

Uncertain Significance for BRCA2-related cancer predisposition. Applied ACMG criteria (verbatim):

PS3 PP3

Curation rationale (ClinGen, verbatim)

The c.8059G>T variant in BRCA2 is a missense variant predicted to cause substitution of Valine by Phenylalanine at amino acid 2687 (p.(Val2687Phe)). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.37, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 39779857, 39779848) (PS3 met). mRNA experimental analysis indicates no impact on splicing (Internal lab contributor) but is not applied as strong evidence against pathogenicity since missense impact has not been excluded (BP7_Strong (RNA) not met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.42 (based on Family History LR=1.42), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PS3, PP3).

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

Variant & gene context

Gene: BRCA2
Protein: p.Val2687Phe
Coding: c.8059G>T
MANE Select: NM_000059
dbSNP: rs80359044
Type: single nucleotide variant
Location: chr13:32363261 (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

Also linked: hereditary breast ovarian cancer syndrome breast-ovarian cancer, familial, susceptibility to, 2 hereditary neoplastic syndrome

Similar variants

BRCA2 p.Val2687= Likely benign ★★★ same residue
BRCA2 p.Val2687Ala Uncertain significance ★★ ⚠ same residue
BRCA2 p.Val2687Ile Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Val2687fs Pathogenic ★★★ 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

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-val2687phe (accessed [today's date]).

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