Is BRCA2 c.682-2A>C pathogenic?

BRCA2 c.682-2A>C is classified Pathogenic/Likely pathogenic in BRCA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-07-12). Absent from gnomAD v4.1; Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 c.682-2A>C?

BRCA2 c.682-2A>C is associated with breast-ovarian cancer, familial, susceptibility to, 2, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 c.682-2A>C in the general population?

BRCA2 c.682-2A>C 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 c.682-2A>C

rs878853287 · VCV267659

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

canonical splice-site (±1/±2)

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/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
Splicing
Splice region	acceptor -2	canonical splice dinucleotide (acceptor -2) · inside the BP7-excluded zone
SpliceAI	Δ1.00	acceptor loss, 2 bp away · raw score · deltas
Pangolin	Δ0.87	loss · gain 0.06 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Non-coding constraint	Z 1.14	1 kb window · o/e 0.91 · regional · uncalibrated
Overall
CADD	26.9	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
Coding: c.682-2A>C
MANE Select: NM_000059
dbSNP: rs878853287
Type: single nucleotide variant
Location: chr13:32330917 (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

Also linked: hereditary breast ovarian cancer syndrome hereditary neoplastic syndrome

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-682-minus-2a-c (accessed [today's date]).

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