Is BRCA2 p.Arg2896Ser (c.8686C>A) pathogenic?

BRCA2 p.Arg2896Ser (c.8686C>A) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-23). AlphaMissense: likely benign (0.2007); Very rare (popmax 0.000339%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Arg2896Ser (c.8686C>A)?

BRCA2 p.Arg2896Ser (c.8686C>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.Arg2896Ser (c.8686C>A) in the general population?

BRCA2 p.Arg2896Ser (c.8686C>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about BRCA2 p.Arg2896Ser (c.8686C>A)?

AlphaMissense predicts likely benign (score 0.2007) — an in-silico prediction, not a clinical call.

BRCA2 p.Arg2896Ser

c.8686C>A · rs373203204 · VCV645800

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2007 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2007	likely benign
REVEL	0.19	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
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	14.07	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 0.000339% European (non-Finnish) · 4/1,179,994 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,092 alleles · very rare exomes 4/1,461,842 · genomes 0/152,250 · joint denominator

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.Arg2896Ser
Coding: c.8686C>A
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

Similar variants

BRCA2 p.Arg2896Cys Conflicting classifications of pathogenicity ★ ⚠ 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.Arg2896fs Pathogenic ★ same residue
BRCA2 p.Arg2896= Likely benign ★★★ 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-arg2896ser (accessed [today's date]).

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