Is BRCA2 c.8331+3A>C pathogenic?

BRCA2 c.8331+3A>C is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-07-31). Very rare (popmax 0.00535%, afr); Associated with Wilms tumor 1.

What condition is associated with BRCA2 c.8331+3A>C?

BRCA2 c.8331+3A>C is associated with Wilms tumor 1, hereditary breast ovarian cancer syndrome, medulloblastoma (ClinVar).

How common is BRCA2 c.8331+3A>C in the general population?

BRCA2 c.8331+3A>C is very rare (popmax 0.00535%, afr) (gnomAD).

BRCA2 c.8331+3A>C

rs876659382 · VCV231812

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00535%, afr)

Conditions

Wilms tumor 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
Splice region	donor +3	donor splice region (+3, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	Δ0.71	donor loss · deltas
Pangolin	Δ0.69	loss · gain 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.8	GERP -1.3, phastCons 1
Non-coding constraint	Z 0.81	1 kb window · o/e 0.94 · regional · uncalibrated
Overall
CADD	14.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00535% African / African-American · 4/74,816 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,609,992 alleles · very rare exomes 1/1,457,804 · genomes 3/152,188 · 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
Coding: c.8331+3A>C
MANE Select: NM_000059
dbSNP: rs876659382
Type: single nucleotide variant
Location: chr13:32363536 (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

Wilms tumor 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome medulloblastoma prostate cancer Fanconi anemia complementation group D1 breast-ovarian cancer, familial, susceptibility to, 2 glioma susceptibility 3 pancreatic cancer, susceptibility to, 2 hereditary neoplastic syndrome hereditary breast carcinoma

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-8331-plus-3a-c (accessed [today's date]).

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