Is BRCA2 p.Gln754Ter (c.2260C>T) pathogenic?

BRCA2 p.Gln754Ter (c.2260C>T) is classified Pathogenic in BRCA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-17). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Gln754Ter (c.2260C>T)?

BRCA2 p.Gln754Ter (c.2260C>T) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.Gln754Ter (c.2260C>T) in the general population?

BRCA2 p.Gln754Ter (c.2260C>T) is absent from gnomAD v4.1 (gnomAD).

BRCA2 p.Gln754Ter

c.2260C>T · rs80358496 · VCV2994101

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -1.6, phastCons 0.003
Overall
CADD	29.0	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.Gln754Ter
Coding: c.2260C>T
MANE Select: NM_000059
dbSNP: rs80358496
Type: single nucleotide variant
Location: chr13:32336615 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 754: the 'interaction with npm1' region

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.Gln754= Likely benign ★★★ same residue
BRCA2 p.Gln754Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Gln754Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Gln754Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Gln754fs 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

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-gln754ter (accessed [today's date]).

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