Is BRCA1 p.Cys61Gly (c.181T>G) pathogenic?

BRCA1 p.Cys61Gly (c.181T>G) is classified Pathogenic in BRCA1 (ClinVar, Expert panel, 69 submitters; last evaluated 2015-08-10). AlphaMissense: likely pathogenic (0.9904); Very rare (popmax 0.00239%, nfe); Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with BRCA1 p.Cys61Gly (c.181T>G)?

BRCA1 p.Cys61Gly (c.181T>G) is associated with breast-ovarian cancer, familial, susceptibility to, 1, hereditary breast ovarian cancer syndrome, breast carcinoma (ClinVar).

How common is BRCA1 p.Cys61Gly (c.181T>G) in the general population?

BRCA1 p.Cys61Gly (c.181T>G) is very rare (popmax 0.00239%, nfe) (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.

What do computational predictors say about BRCA1 p.Cys61Gly (c.181T>G)?

AlphaMissense predicts likely pathogenic (score 0.9904) — an in-silico prediction, not a clinical call.

BRCA1 p.Cys61Gly

c.181T>G · rs28897672 · VCV17661

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 69 submitters

AlphaMissense

likely pathogenic

0.9904 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00239%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

breast-ovarian cancer, familial, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.9904	likely pathogenic ✓ concordant with ClinVar · top 1% in BRCA1
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -12.21	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00239% European (non-Finnish) · 28/1,172,588 alleles

Filtering AF 0.00166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00143%

Overall 0.00187% 30/1,604,818 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00239%	41,878
Remaining individualsnot grpmax-eligible	0.00161%	62,106
Finnishnot grpmax-eligible	0.00156%	63,978

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.Cys61Gly
Coding: c.181T>G
MANE Select: NM_007294
dbSNP: rs28897672
Type: single nucleotide variant
Location: chr17:43106487 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 61: a UniProt-annotated variant site (in bc and oc; pathogenic; no interaction with bap1)

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

Also linked: hereditary breast ovarian cancer syndrome breast carcinoma pancreatic cancer, susceptibility to, 4 hereditary neoplastic syndrome hereditary breast carcinoma ovarian neoplasm breast neoplasm Fanconi anemia, complementation group S BRCA1-related cancer predisposition

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Cys61Arg Pathogenic/Likely pathogenic ★★ same residue
BRCA1 p.Cys61Ser Pathogenic ★★ same residue
BRCA1 p.Cys61Tyr Pathogenic ★★ same residue
BRCA1 p.Cys61= Likely benign ★★ same residue
BRCA1 p.Cys61Phe Uncertain significance ★ ⚠ same residue
BRCA1 p.Cys61fs Pathogenic ★★★ same residue
BRCA1 c.134+3A>T Likely pathogenic ★★★ same condition
BRCA1 c.135-1G>T 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-cys61gly (accessed [today's date]).

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