Is BRCA2 p.Arg2991Cys (c.8971C>T) pathogenic?

BRCA2 p.Arg2991Cys (c.8971C>T) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-03-19). AlphaMissense: likely benign (0.2026); Very rare (popmax 0.00446%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Arg2991Cys (c.8971C>T)?

BRCA2 p.Arg2991Cys (c.8971C>T) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Arg2991Cys (c.8971C>T) in the general population?

BRCA2 p.Arg2991Cys (c.8971C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about BRCA2 p.Arg2991Cys (c.8971C>T)?

AlphaMissense predicts likely benign (score 0.2026) — an in-silico prediction, not a clinical call.

BRCA2 p.Arg2991Cys

c.8971C>T · rs751787816 · VCV489793

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2026 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2026	likely benign
REVEL	0.555	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.27 · evaluated, not missing
Pangolin	Δ0.20	loss · gain 0.10 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 2.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,836 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.00031% 5/1,611,520 alleles · very rare exomes 5/1,459,270 · genomes 0/152,250 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,418
Remaining individualsnot grpmax-eligible	0.0016%	62,408
European (non-Finnish)	0.00017%	588,862

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.Arg2991Cys
Coding: c.8971C>T
MANE Select: NM_000059
dbSNP: rs751787816
Type: single nucleotide variant
Location: chr13:32379767 (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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome breast-ovarian cancer, familial, susceptibility to, 2 BRCA2-related cancer predisposition

Similar variants

BRCA2 p.Arg2991Pro Uncertain significance ★★ ⚠ same residue
BRCA2 p.Arg2991= Likely benign ★★ same residue
BRCA2 p.Arg2991His Benign/Likely benign ★★ same residue
BRCA2 p.Arg2991Leu 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
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-arg2991cys (accessed [today's date]).

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