Is BRCA1 c.301+12A>C pathogenic?

BRCA1 c.301+12A>C is classified Benign/Likely benign in BRCA1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-16). Very rare (popmax 0.00333%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 c.301+12A>C?

BRCA1 c.301+12A>C is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRCA1 c.301+12A>C in the general population?

BRCA1 c.301+12A>C is very rare (popmax 0.00333%, amr) (gnomAD).

BRCA1 c.301+12A>C

rs863224757 · VCV216660

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +12	near-intronic (+12 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.13	GERP -3.7
Non-coding constraint	Z 0.28	1 kb window · o/e 0.98 · regional · uncalibrated
Overall
CADD	3.657	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,972 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000373% 6/1,608,442 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,986
European (non-Finnish)	0.00034%	293,783

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: BRCA1
Coding: c.301+12A>C
MANE Select: NM_007294
dbSNP: rs863224757
Type: single nucleotide variant
Location: chr17:43104856 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB

Full BRCA1 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 cancer breast-ovarian cancer, familial, susceptibility to, 1

Similar variants

BRCA1 c.134+3A>T Likely pathogenic ★★★ same condition
BRCA1 c.135-1G>T Pathogenic ★★★ same condition
BRCA1 c.212+1G>A Pathogenic ★★★ same condition
BRCA1 c.212+1G>T Pathogenic ★★★ same condition
BRCA1 c.212+3A>G Pathogenic ★★★ same condition
BRCA1 c.213-12A>G Pathogenic ★★★ same condition
BRCA1 c.213-15A>G Likely pathogenic ★★★ same condition
BRCA1 c.302-1G>C 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/brca1-c-301-plus-12a-c (accessed [today's date]).

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