Is BRCA2 p.Gly2281Ter (c.6841G>T) pathogenic?

BRCA2 p.Gly2281Ter (c.6841G>T) is classified Likely pathogenic in BRCA2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-07-21). Absent from gnomAD v4.1; Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Gly2281Ter (c.6841G>T)?

BRCA2 p.Gly2281Ter (c.6841G>T) is associated with breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Gly2281Ter (c.6841G>T) in the general population?

BRCA2 p.Gly2281Ter (c.6841G>T) is absent from gnomAD v4.1 (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.

BRCA2 p.Gly2281Ter

c.6841G>T · rs1390926046 · VCV2574094

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

breast-ovarian cancer, familial, susceptibility to, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 11 of 27
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.80 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BRCA2
Protein: p.Gly2281Ter
Coding: c.6841G>T
MANE Select: NM_000059
dbSNP: rs1390926046
Type: single nucleotide variant
Location: chr13:32341196 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2281: the 'interaction with hsf2bp' region

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

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Gly2281Glu Uncertain significance ★★ ⚠ same residue
BRCA2 p.Gly2281Val Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Gly2281= Likely benign ★★ same residue
BRCA2 p.Gly2281Arg Uncertain significance ★ 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

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-gly2281ter (accessed [today's date]).

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