Is BRCA2 c.425+246G>C pathogenic?

BRCA2 c.425+246G>C is classified Benign in BRCA2 (ClinVar, Expert panel, 3 submitters; last evaluated 2015-01-12). Common (popmax 39.8%, eas) — too common for a highly-penetrant pathogenic allele; Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 c.425+246G>C?

BRCA2 c.425+246G>C is associated with breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

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 c.425+246G>C

Q: How common is BRCA2 c.425+246G>C in the general population?

BRCA2 c.425+246G>C is common (popmax 39.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs11571613 · VCV209644

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 39.8%, eas) — too common for a highly-penetrant pathogenic allele

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.
Splicing
Splice region	donor +246	deep intronic (+246 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.18	GERP -0.92
Overall
CADD	8.896	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 39.8% East Asian · 2,058/5,172 alleles

Filtering AF 38.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 37.8%

Overall 27.7% 42,106/151,886 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	39.8%	3
European (non-Finnish)	31.3%	3
Ashkenazi Jewishnot grpmax-eligible	30.7%	3
Middle Eastern	29.6%	3
South Asian	29.2%	3
Remaining individualsnot grpmax-eligible	27.1%	4
Finnishnot grpmax-eligible	24.4%	4
African / African-American	23%	4
Admixed American	22.3%	4
Amishnot grpmax-eligible	17.8%	6

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
Coding: c.425+246G>C
MANE Select: NM_000059
dbSNP: rs11571613
Type: single nucleotide variant
Location: chr13:32325430 (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 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
BRCA2 c.475+1G>A Pathogenic ★★★ same condition
BRCA2 c.475+1G>T Pathogenic ★★★ same condition
BRCA2 c.476-2A>G Pathogenic ★★★ same condition
BRCA2 c.517-2A>G 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-c-425-plus-246g-c (accessed [today's date]).

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