Is BRCA2 c.681+4A>T pathogenic?

BRCA2 c.681+4A>T is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-18). Very rare (popmax 6.96e-05%); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 c.681+4A>T?

BRCA2 c.681+4A>T is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 c.681+4A>T in the general population?

BRCA2 c.681+4A>T is very rare (popmax 6.96e-05%) (gnomAD).

BRCA2 c.681+4A>T

rs397507884 · VCV233034

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 6.96e-05%)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
Splice region	donor +4	donor splice region (+4, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	Δ0.29	acceptor loss, 49 bp away · raw score · deltas
Pangolin	Δ0.77	loss · gain 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.8	GERP 1.1, phastCons 1
Non-coding constraint	Z 1.29	1 kb window · o/e 0.90 · regional · uncalibrated
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.96e-05%

Overall 6.96e-05% 1/1,436,736 alleles · very rare

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.681+4A>T
MANE Select: NM_000059
dbSNP: rs397507884
Type: single nucleotide variant
Location: chr13:32329496 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome breast-ovarian cancer, familial, susceptibility to, 2 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-681-plus-4a-t (accessed [today's date]).

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