Is BRCA2 p.Arg2896Cys (c.8686C>T) pathogenic?

BRCA2 p.Arg2896Cys (c.8686C>T) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0802); Ultra-rare (popmax 0.0198%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Arg2896Cys (c.8686C>T)?

BRCA2 p.Arg2896Cys (c.8686C>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.Arg2896Cys (c.8686C>T) in the general population?

BRCA2 p.Arg2896Cys (c.8686C>T) is ultra-rare (popmax 0.0198%, sas) (gnomAD).

What do computational predictors say about BRCA2 p.Arg2896Cys (c.8686C>T)?

AlphaMissense predicts likely benign (score 0.0802) — an in-silico prediction, not a clinical call.

BRCA2 p.Arg2896Cys

c.8686C>T · rs373203204 · VCV231378

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.0802 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0198%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0802	likely benign
REVEL	0.248	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 0.21	GERP -3.9
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	16.59	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 0.0198% South Asian · 18/91,076 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00173% 28/1,614,092 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0198%	5,060
Admixed American	0.00167%	60,014
Remaining individualsnot grpmax-eligible	0.0016%	62,504
Finnishnot grpmax-eligible	0.00156%	64,028
European (non-Finnish)	0.000593%	168,571

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.Arg2896Cys
Coding: c.8686C>T
MANE Select: NM_000059
dbSNP: rs373203204
Type: single nucleotide variant
Location: chr13:32376723 (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 hereditary breast carcinoma

Similar variants

BRCA2 p.Arg2896= Likely benign ★★★ same residue
BRCA2 p.Arg2896Gly Uncertain significance ★ ⚠ same residue
BRCA2 p.Arg2896His Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Arg2896Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Arg2896Pro Uncertain significance ★ same residue
BRCA2 p.Arg2896Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Arg2896fs Pathogenic ★ same residue
BRCA2 c.316+1G>T 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-arg2896cys (accessed [today's date]).

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