Is BRCA2 p.Ser286Pro (c.856T>C) pathogenic?

BRCA2 p.Ser286Pro (c.856T>C) is classified Likely benign in BRCA2 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-03-23). AlphaMissense: likely benign (0.0978); Very rare (popmax 0.00522%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Ser286Pro (c.856T>C)?

BRCA2 p.Ser286Pro (c.856T>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Ser286Pro (c.856T>C) in the general population?

BRCA2 p.Ser286Pro (c.856T>C) is very rare (popmax 0.00522%, amr) (gnomAD).

What do computational predictors say about BRCA2 p.Ser286Pro (c.856T>C)?

AlphaMissense predicts likely benign (score 0.0978) — an in-silico prediction, not a clinical call.

BRCA2 p.Ser286Pro

c.856T>C · rs80359111 · VCV52622

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.0978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00522%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0978	likely benign
REVEL	0.226	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.27	GERP -1.6
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	14.41	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 0.00522% Admixed American · 3/57,486 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00175% 28/1,601,596 alleles · very rare exomes 26/1,449,448 · genomes 2/152,148 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00522%	19,162
European (non-Finnish)	0.00196%	51,091
Remaining individualsnot grpmax-eligible	0.00161%	61,968
African / African-American	0.00135%	74,168

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.Ser286Pro
Coding: c.856T>C
MANE Select: NM_000059
dbSNP: rs80359111
Type: single nucleotide variant
Location: chr13:32332334 (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

Similar variants

BRCA2 p.Ser286Ter Pathogenic ★★★ 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
BRCA2 c.475+1G>T Pathogenic ★★★ same condition
BRCA2 c.476-2A>G 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-ser286pro (accessed [today's date]).

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