Is BRCA1 c.593+3G>A pathogenic?

BRCA1 c.593+3G>A is classified Conflicting classifications of pathogenicity in BRCA1 (ClinVar, Conflicting submitters, 17 submitters; last evaluated 2026-07-29). Ultra-rare (popmax 0.033%, mid); Associated with Inherited breast cancer and ovarian cancer.

What condition is associated with BRCA1 c.593+3G>A?

BRCA1 c.593+3G>A is associated with Inherited breast cancer and ovarian cancer, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 c.593+3G>A in the general population?

BRCA1 c.593+3G>A is ultra-rare (popmax 0.033%, mid) (gnomAD).

BRCA1 c.593+3G>A

rs80358013 · VCV91657

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 17 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

Inherited breast cancer and ovarian cancer

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +3	donor splice region (+3, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.48 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.088	GERP -0.31, phastCons 0.92
Non-coding constraint	Z 2.23	1 kb window · o/e 0.80 · regional · uncalibrated
Overall
CADD	15.59	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.00186% 30/1,613,494 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,030
African / African-American	0.032%	3,126
Remaining individualsnot grpmax-eligible	0.0048%	20,825
South Asian	0.0011%	90,926

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.593+3G>A
MANE Select: NM_007294
dbSNP: rs80358013
Type: single nucleotide variant
Location: chr17:43097241 (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

Inherited breast cancer and ovarian cancer

Also linked: hereditary breast ovarian cancer syndrome breast-ovarian cancer, familial, susceptibility to, 1 hereditary neoplastic syndrome

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-593-plus-3g-a (accessed [today's date]).

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