Is BRCA2 p.Pro412fs (c.1233dup) pathogenic?

BRCA2 p.Pro412fs (c.1233dup) is classified Pathogenic in BRCA2 (ClinVar, Expert panel, 5 submitters; last evaluated 2016-09-08). Ultra-rare (popmax 0.0165%, mid); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Pro412fs (c.1233dup)?

BRCA2 p.Pro412fs (c.1233dup) is associated with breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Pro412fs (c.1233dup) in the general population?

BRCA2 p.Pro412fs (c.1233dup) is ultra-rare (popmax 0.0165%, mid) (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.Pro412fs

c.1233dup · rs80359270 · VCV51088

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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 10 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.5	GERP -4.6

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,056 alleles

Overall 6.2e-05% 1/1,613,656 alleles · ultra-rare exomes 1/1,461,474 · genomes 0/152,182 · joint denominator

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.Pro412fs
Coding: c.1233dup
MANE Select: NM_000059
dbSNP: rs80359270
Type: Duplication
Location: chr13:32332710 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)

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.Pro412= Likely benign ★★★ same residue
BRCA2 p.Pro412Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro412Thr Conflicting classifications of pathogenicity ★ ⚠ 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
BRCA2 c.7806-2_7806-1dup 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-pro412fs (accessed [today's date]).

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