Is BRCA2 p.Ser976del (c.2927_2929del) pathogenic?

BRCA2 p.Ser976del (c.29272929del) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-12-23). Very rare (popmax 0.00168%, amr); Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Ser976del (c.2927_2929del)?

BRCA2 p.Ser976del (c.2927_2929del) is associated with BRCA2-related cancer predisposition, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Ser976del (c.2927_2929del) in the general population?

BRCA2 p.Ser976del (c.2927_2929del) is very rare (popmax 0.00168%, amr) (gnomAD).

BRCA2 p.Ser976del

c.2927_2929del · rs80359363 · VCV51373

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Conditions

BRCA2-related cancer predisposition

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.37	GERP -4.6

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00168% Admixed American · 1/59,624 alleles

Filtering AF 0.000543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.000868% 14/1,611,980 alleles · very rare exomes 14/1,459,726 · genomes 0/152,254 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00168%	59,624
South Asian	0.0011%	90,530
European (non-Finnish)	0.00102%	98,282

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.Ser976del
Coding: c.2927_2929del
MANE Select: NM_000059
dbSNP: rs80359363
Type: Deletion
Location: chr13:32337280 (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

Also linked: hereditary breast ovarian cancer syndrome breast-ovarian cancer, familial, susceptibility to, 2 hereditary neoplastic syndrome

Similar variants

BRCA2 p.Ser976_Leu977insTer Pathogenic ★★★ same residue
BRCA2 p.Ser976= Likely benign ★★ same residue
BRCA2 p.Ser976Phe Benign/Likely benign ★★ same residue
BRCA2 p.Ser976Thr Benign/Likely benign ★★ same residue
BRCA2 p.Ser976fs Pathogenic ★ same residue
BRCA2 p.Ser976Ile Conflicting classifications of pathogenicity ★ same residue
BRCA2 c.316+4del Pathogenic ★★★ same condition
BRCA2 c.5217_5224del 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-ser976del (accessed [today's date]).

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