Is BRCA2 p.Glu3343Val (c.10028A>T) pathogenic?

BRCA2 p.Glu3343Val (c.10028A>T) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-10). AlphaMissense: likely pathogenic (0.7073); Very rare (popmax 0.000434%); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Glu3343Val (c.10028A>T)?

BRCA2 p.Glu3343Val (c.10028A>T) is associated with hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is BRCA2 p.Glu3343Val (c.10028A>T) in the general population?

BRCA2 p.Glu3343Val (c.10028A>T) is very rare (popmax 0.000434%) (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.Glu3343Val (c.10028A>T)?

AlphaMissense predicts likely pathogenic (score 0.7073) — an in-silico prediction, not a clinical call.

BRCA2 p.Glu3343Val

c.10028A>T · rs772432857 · VCV1770793

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.7073 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000434%)

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.7073	likely pathogenic · top 5% in BRCA2
REVEL	0.313	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	26.6	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

Grpmax group 0.000434%

Overall 0.000434% 7/1,614,100 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.

Variant & gene context

Gene: BRCA2
Protein: p.Glu3343Val
Coding: c.10028A>T
MANE Select: NM_000059
dbSNP: rs772432857
Type: single nucleotide variant
Location: chr13:32398541 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)

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 hereditary breast carcinoma

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Glu3343= Likely benign ★★★ same residue
BRCA2 p.Glu3343Lys Uncertain significance ★ same residue
BRCA2 p.Glu3343Ter Likely benign ★ 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-glu3343val (accessed [today's date]).

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