Is BRCA1 c.4357+1212T>C pathogenic?

BRCA1 c.4357+1212T>C is classified Benign in BRCA1 (ClinVar, Expert panel, 2 submitters; last evaluated 2015-01-12). Low-frequency (popmax 1%, afr); Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with BRCA1 c.4357+1212T>C?

BRCA1 c.4357+1212T>C is associated with breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 c.4357+1212T>C in the general population?

BRCA1 c.4357+1212T>C is low-frequency (popmax 1%, afr) (gnomAD).

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+1212T>C

rs8176187 · VCV209408

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1%, afr)

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 +1212	deep intronic (+1212 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP -0.46, phastCons 1
Non-coding constraint	Z 1.33	1 kb window · o/e 0.89 · regional · uncalibrated
Overall
CADD	13.81	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1% African / African-American · 417/41,580 alleles

Filtering AF 0.923% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.892%

Overall 0.431% 657/152,358 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1%	100
Admixed American	0.784%	128
Middle Eastern	0.68%	147
Remaining individualsnot grpmax-eligible	0.614%	163
European (non-Finnish)	0.147%	680
Ashkenazi Jewishnot grpmax-eligible	0.0865%	1,156
South Asian	0.0207%	4,830
Finnishnot grpmax-eligible	0.00941%	10,628

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+1212T>C
MANE Select: NM_007294
dbSNP: rs8176187
Type: single nucleotide variant
Location: chr17:43081192 (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-1212t-c (accessed [today's date]).

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