Is BRCA2 p.Ser976Phe (c.2927C>T) pathogenic?

BRCA2 p.Ser976Phe (c.2927C>T) is classified Benign/Likely benign in BRCA2 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-01-23). AlphaMissense: likely benign (0.1362); Rare (popmax 0.681%, afr); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Ser976Phe (c.2927C>T)?

BRCA2 p.Ser976Phe (c.2927C>T) is associated with breast-ovarian cancer, familial, susceptibility to, 2, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Ser976Phe (c.2927C>T) in the general population?

BRCA2 p.Ser976Phe (c.2927C>T) is rare (popmax 0.681%, afr) (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.Ser976Phe (c.2927C>T)?

AlphaMissense predicts likely benign (score 0.1362) — an in-silico prediction, not a clinical call.

BRCA2 p.Ser976Phe

c.2927C>T · rs11571656 · VCV434528

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.1362 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.681%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

breast-ovarian cancer, familial, susceptibility to, 2

Computational evidence

Protein change
AlphaMissense	0.1362	likely benign
REVEL	0.134	moderately 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 0.88	GERP -0.45
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	14.47	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 0.681% African / African-American · 510/74,838 alleles

Filtering AF 0.633% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.613%

Overall 0.035% 564/1,612,378 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.681%	147
Remaining individualsnot grpmax-eligible	0.0449%	2,229
Admixed American	0.0385%	2,597
European (non-Finnish)	0.000254%	393,164

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.Ser976Phe
Coding: c.2927C>T
MANE Select: NM_000059
dbSNP: rs11571656
Type: single nucleotide variant
Location: chr13:32337282 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 976: the 'interaction with npm1' region; a UniProt-annotated variant site (in)

Full BRCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

breast-ovarian cancer, familial, susceptibility to, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome hereditary neoplastic syndrome

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Ser976= Likely benign ★★ same residue
BRCA2 p.Ser976Thr Benign/Likely benign ★★ same residue
BRCA2 p.Ser976_Leu977insTer Pathogenic ★★★ same residue
BRCA2 p.Ser976del Uncertain significance ★★ same residue
BRCA2 p.Ser976fs Pathogenic ★ same residue
BRCA2 p.Ser976Ile Conflicting classifications of pathogenicity ★ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>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-ser976phe (accessed [today's date]).

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