Is BRCA2 p.Glu3316Val (c.9947A>T) pathogenic?

BRCA2 p.Glu3316Val (c.9947A>T) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-06). AlphaMissense: likely benign (0.0926); Absent from gnomAD v4.1; Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Glu3316Val (c.9947A>T)?

BRCA2 p.Glu3316Val (c.9947A>T) is associated with hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Glu3316Val (c.9947A>T) in the general population?

BRCA2 p.Glu3316Val (c.9947A>T) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BRCA2 p.Glu3316Val (c.9947A>T)?

AlphaMissense predicts likely benign (score 0.0926) — an in-silico prediction, not a clinical call.

BRCA2 p.Glu3316Val

c.9947A>T · rs1555290010 · VCV489803

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0926 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.0926	likely benign
REVEL	0.085	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -1.8, phastCons 0.29
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	18.67	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

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

Variant & gene context

Gene: BRCA2
Protein: p.Glu3316Val
Coding: c.9947A>T
MANE Select: NM_000059
dbSNP: rs1555290010
Type: single nucleotide variant
Location: chr13:32398460 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 3316: the 'tr2 region' region

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

Disease context

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

Also linked: hereditary neoplastic syndrome

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Glu3316Ter Uncertain significance ★★★ same residue
BRCA2 p.Glu3316Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Glu3316= Likely benign ★ same residue
BRCA2 p.Glu3316del Uncertain significance ★ same residue
BRCA2 p.Glu3316Gly 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

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-glu3316val (accessed [today's date]).

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