BRCA1 p.Trp1718Ser
c.5153G>C · rs41293461 · VCV55433
ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP
Uncertain Significance for BRCA1-related cancer predisposition. Applied ACMG criteria (verbatim):
PM2_Supporting PP3 PP4
Curation rationale (ClinGen, verbatim)
The c.5153G>C variant in BRCA1 is a missense variant predicted to cause substitution of Tryptophan by Serine at amino acid 1718 (p.(Trp1718Ser)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.52, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.14 indicates an unclear predicted impact on splicing (score threshold 0.10-0.20) (PP3 met). Reported by two or more calibrated studies with discordant results. Functional effect similar to pathogenic control variants (PMID:38709234) and between what was observed for benign and pathogenic control variants (PMID:30209399) (PS3 and BS3 not met). mRNA experimental analysis indicates no impact on splicing (PMID: 25724305) but is not applied as strong evidence against pathogenicity since missense impact has not yet been excluded (BP7_Strong (RNA) not met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3.32 (based on Co-occurrence LR=1.03; Family History LR=3.22), within the thresholds for supporting evidence towards pathogenicity (LR >2.08 & ≤4.3) (PP4 met; Internal lab contributor). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PP4).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9365 | likely pathogenic · top 2% in BRCA1 |
|---|---|---|
| REVEL | 0.914 | moderately pathogenic-leaning |
| SaProt | LLR -13.68 | 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 7.6 | GERP 2.6, phastCons 1 |
| Regional constraint | o/e 0.91 | unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic |
| Overall | ||
| CADD | 32.0 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
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.Trp1718Ser
- Coding
- c.5153G>C
- MANE Select
- NM_007294
- dbSNP
- rs41293461
- Type
- single nucleotide variant
- Location
- chr17:43063373 (GRCh38)
- Gene constraint
- LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 41.99 · 33 PDB
- Residue 1718
- the brct 1 domain; a UniProt-annotated variant site (in fancs); a UniProt-annotated variant site (in bc; uncertain significance; functionally impaired in vitro); an α-helix
Similar variants
- BRCA1 p.Trp1718Gly Likely pathogenic ★★★ same residue
- BRCA1 p.Trp1718Ter Pathogenic ★★★ same residue
- BRCA1 p.Trp1718Cys Pathogenic/Likely pathogenic ★★ same residue
- BRCA1 p.Trp1718Leu Uncertain significance ⚠ same residue
- BRCA1 p.Trp1718fs Pathogenic same residue
- BRCA1 p.Trp1718Arg Uncertain significance ★ ⚠ 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-trp1718ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown