Is BRCA1 c.4357+2519C>T pathogenic?

BRCA1 c.4357+2519C>T is classified Benign in BRCA1 (ClinVar, Expert panel, 2 submitters; last evaluated 2015-01-12). Common (popmax 49.9%, sas) — too common for a highly-penetrant pathogenic allele; Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with BRCA1 c.4357+2519C>T?

BRCA1 c.4357+2519C>T is associated with breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

BRCA1 c.4357+2519C>T

Q: How common is BRCA1 c.4357+2519C>T in the general population?

BRCA1 c.4357+2519C>T is common (popmax 49.9%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs4793197 · VCV209401

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 49.9%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

breast-ovarian cancer, familial, susceptibility to, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +2519	deep intronic (+2519 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.031	GERP -2.1
Non-coding constraint	Z -1.03	1 kb window · o/e 1.08 · regional · uncalibrated
Overall
CADD	1.016	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 49.9% South Asian · 28,665/57,462 alleles

Filtering AF 49.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 49.2%

Overall 33.8% 219,753/650,874 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	49.9%	2
Finnishnot grpmax-eligible	39.6%	3
Middle Eastern	37.8%	3
Ashkenazi Jewishnot grpmax-eligible	35.6%	3
East Asian	35.3%	3
Remaining individualsnot grpmax-eligible	33.2%	3
European (non-Finnish)	32.8%	3
Admixed American	32.3%	3
Amishnot grpmax-eligible	28.5%	4
African / African-American	18.1%	6

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.4357+2519C>T
MANE Select: NM_007294
dbSNP: rs4793197
Type: single nucleotide variant
Location: chr17:43079885 (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

breast-ovarian cancer, familial, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

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-4357-plus-2519c-t (accessed [today's date]).

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