Is BRCA2 p.Arg3269Ser (c.9807A>C) pathogenic?

BRCA2 p.Arg3269Ser (c.9807A>C) is classified Uncertain significance in BRCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-06). AlphaMissense: ambiguous (0.3993); Absent from gnomAD v4.1; Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Arg3269Ser (c.9807A>C)?

BRCA2 p.Arg3269Ser (c.9807A>C) is associated with hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.Arg3269Ser (c.9807A>C) in the general population?

BRCA2 p.Arg3269Ser (c.9807A>C) 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.Arg3269Ser (c.9807A>C)?

AlphaMissense predicts ambiguous (score 0.3993) — an in-silico prediction, not a clinical call.

BRCA2 p.Arg3269Ser

c.9807A>C · rs2137663968 · VCV2107431

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.3993	ambiguous
REVEL	0.195	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP -0.63, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	19.49	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

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.Arg3269Ser
Coding: c.9807A>C
MANE Select: NM_000059
dbSNP: rs2137663968
Type: single nucleotide variant
Location: chr13:32398320 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 3269: 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

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Arg3269Gly Uncertain significance ★★ ⚠ same residue
BRCA2 p.Arg3269Ile Uncertain significance ★★ ⚠ same residue
BRCA2 p.Arg3269Lys Uncertain significance ★★ ⚠ same residue
BRCA2 p.Arg3269Thr Uncertain significance ★★ ⚠ same residue
BRCA2 p.Arg3269fs Pathogenic ★ same residue
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-arg3269ser (accessed [today's date]).

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