Is BRCA2 p.Val726fs (c.2175dup) pathogenic?

BRCA2 p.Val726fs (c.2175dup) is classified Pathogenic in BRCA2 (ClinVar, Expert panel, 10 submitters; last evaluated 2016-09-08). Ultra-rare (gnomAD MAF 1.679e-06); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Val726fs (c.2175dup)?

BRCA2 p.Val726fs (c.2175dup) is associated with breast-ovarian cancer, familial, susceptibility to, 2, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Val726fs (c.2175dup) in the general population?

BRCA2 p.Val726fs (c.2175dup) is ultra-rare (gnomAD MAF 1.679e-06) (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.Val726fs

c.2175dup · rs276174819 · VCV37776

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (gnomAD MAF 1.679e-06)

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	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 11 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.35	GERP -4.6

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

Population frequency

dbSNP / gnomAD

Global frequency 0.000168% via dbSNP · ultra-rare

No ancestry breakdown or filtering allele frequency is available for this variant, so BA1/BS1 cannot be assessed from this figure alone.

Variant & gene context

Gene: BRCA2
Protein: p.Val726fs
Coding: c.2175dup
MANE Select: NM_000059
dbSNP: rs276174819
Type: Duplication
Location: chr13:32336524 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 726: the 'interaction with npm1' 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

Also linked: hereditary breast ovarian cancer syndrome hereditary neoplastic syndrome breast neoplasm

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Val726Ala Uncertain significance ★★ ⚠ same residue
BRCA2 p.Val726Leu Uncertain significance ★★ ⚠ same residue
BRCA2 p.Val726Phe Uncertain significance ★ ⚠ same residue
BRCA2 p.Val726= Likely benign ★ same residue
BRCA2 c.1448_1451dupCAGT Pathogenic ★★★ same condition
BRCA2 c.6081dupA Pathogenic ★★★ same condition
BRCA2 c.6396dupA Pathogenic ★★★ same condition
BRCA2 c.6528_6535dup 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-val726fs (accessed [today's date]).

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