BRCA1 p.Phe1668Ser
c.5003T>C · rs1567772408 · VCV629251
ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP
Uncertain Significance for BRCA1-related cancer predisposition. Applied ACMG criteria (verbatim):
PM2_Supporting PS3
Curation rationale (ClinGen, verbatim)
The c.5003T>C variant in BRCA1 is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 1668 (p.Phe1668Ser). 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 0.24, indicating impact on BRCA1 function via protein change is unclear (score range 0.15-0.28). A SpliceAI score of 0.04 predicts no impact on splicing (score threshold ≤0.1) (no bioinformatic code is applied). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30209399, 38709234) (PS3 met). 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, PS3).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9506 | likely pathogenic · top 2% in BRCA1 |
|---|---|---|
| REVEL | 0.81 | moderately pathogenic-leaning |
| SaProt | LLR -9.98 | tolerated |
| ⇒ AlphaMissense and REVEL call this damaging; SaProt does not. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 11 | GERP 1.6, 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
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.Phe1668Ser
- Coding
- c.5003T>C
- MANE Select
- NM_007294
- dbSNP
- rs1567772408
- Type
- single nucleotide variant
- Location
- chr17:43067679 (GRCh38)
- Gene constraint
- LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 41.99 · 33 PDB
- Residue 1668
- the brct 1 domain; a UniProt-annotated variant site (in fancs); an α-helix
Similar variants
- BRCA1 p.Phe1668Leu Uncertain significance ★★ ⚠ same residue
- BRCA1 p.Phe1668Cys Uncertain significance ★ ⚠ same residue
- BRCA1 p.Phe1668Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
- BRCA1 p.Phe1668Val 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
- BRCA1 c.212+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-phe1668ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown