BRCA1 p.Cys24Ser
c.70T>A · rs80357410 · VCV638952
ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP
Likely Pathogenic for BRCA1-related cancer predisposition. Applied ACMG criteria (verbatim):
PM2_Supporting PS3 PP3
Curation rationale (ClinGen, verbatim)
The variant c.70T>A in BRCA1 is a missense variant predicted to cause substitution of Cysteine by Serine at amino acid 24 (p.Cys24Ser). This variant is absent from gnomAD v4.1 (read depth ≥25x in >90% samples, PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.56, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.02 predicts no impact on splicing (score threshold <0.10) (PP3 met). This variant is reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 30209399) (PS3 met). In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PS3, PM2_Supporting, PP3).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9983 | likely pathogenic ✓ concordant with ClinVar · top 1% in BRCA1 |
|---|---|---|
| REVEL | 0.944 | strongly pathogenic-leaning |
| SaProt | LLR -13.79 | 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 | phastCons 1 |
| Regional constraint | o/e 0.91 | unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic |
| Overall | ||
| CADD | 26.4 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- BRCA1
- Protein
- p.Cys24Ser
- Coding
- c.70T>A
- MANE Select
- NM_007294
- dbSNP
- rs80357410
- Type
- single nucleotide variant
- Location
- chr17:43124027 (GRCh38)
- Gene constraint
- LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 41.99 · 33 PDB
Similar variants
- BRCA1 p.Cys24Tyr Likely pathogenic ★★★ same residue
- BRCA1 p.Cys24Arg Pathogenic/Likely pathogenic ★★ same residue
- BRCA1 p.Cys24Gly Pathogenic/Likely pathogenic ★★ same residue
- BRCA1 p.Cys24Trp Pathogenic ★ same residue
- BRCA1 p.Cys24= Likely benign ★ 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
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-cys24ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown