Is BRCA1 p.Cys197= (c.591C>T) pathogenic?

BRCA1 p.Cys197= (c.591C>T) is classified Benign in BRCA1 (ClinVar, Expert panel, 37 submitters; last evaluated 2024-06-11). Rare (popmax 0.132%, mid); Associated with BRCA1-related cancer predisposition.

What condition is associated with BRCA1 p.Cys197= (c.591C>T)?

BRCA1 p.Cys197= (c.591C>T) is associated with BRCA1-related cancer predisposition, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRCA1 p.Cys197= (c.591C>T) in the general population?

BRCA1 p.Cys197= (c.591C>T) is rare (popmax 0.132%, mid) (gnomAD).

BRCA1 p.Cys197=

c.591C>T · rs1799965 · VCV55642

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 37 submitters

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Conditions

BRCA1-related cancer predisposition

ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP

Benign for BRCA1-related cancer predisposition. Applied ACMG criteria (verbatim):

BP7_Strong BP5_Strong BA1

Curation rationale (ClinGen, verbatim)

The c.591C>T variant in BRCA1 is a synonymous variant (p.Cys197=). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.001402 in the European (non-Finnish) population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This is a synonymous (silent) variant, and mRNA experimental analysis indicates no impact on splicing or an increase of in-frame naturally occurring splice isoforms with production of wildtype transcripts (PMIDs: 19892845, 22505045, 24607278, 23239986), considered strong evidence against pathogenicity (BP7_Strong (RNA)). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.33E-16 (based on Pathology LR=1.33E-16), below the threshold for very strong benign evidence (LR <0.00285) (BP5_Very strong met; ENIGMA internal contributor). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BP7_Strong (RNA), BP5_Very strong).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.20	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 5.6	GERP -0.21, phastCons 1
Overall
CADD	15.93	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.132% Middle Eastern · 8/6,060 alleles

Filtering AF 0.114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.112%

Overall 0.117% 1,893/1,613,468 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.51%	196
Middle Easterngrpmax	0.132%	758
European (non-Finnish)	0.119%	840
Remaining individualsnot grpmax-eligible	0.0784%	1,275
Admixed American	0.0667%	1,500
South Asian	0.044%	2,274
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,289
African / African-American	0.0227%	4,413

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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
Protein: p.Cys197=
Coding: c.591C>T
MANE Select: NM_007294
dbSNP: rs1799965
Type: single nucleotide variant
Location: chr17:43097246 (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

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

Similar variants

BRCA1 p.Cys197Trp Uncertain significance ★ ⚠ same residue
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

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-p-cys197 (accessed [today's date]).

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