BRCA1 p.Tyr1853Asn
c.5557T>A · rs2050860958 · VCV433738
Computational evidence
| Protein change | ||
| AlphaMissense | 0.8579 | likely pathogenic ✓ concordant with ClinVar · top 4% in BRCA1 |
|---|---|---|
| REVEL | 0.835 | moderately pathogenic-leaning |
| SaProt | LLR -14.61 | 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 2.6, phastCons 1 |
| Regional constraint | o/e 0.91 | unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic |
| Overall | ||
| CADD | 26.5 | 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 + genomesAbsent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
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 c.5557T>A variant in BRCA1 is a missense variant predicted to cause substitution of Tyrosine by Asparagine at amino acid 1853 (p.(Tyr1853Asn)). 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 a SpliceAI score of 0 predicts no impact on splicing (score threshold ≤0.1). The computational predictor BayesDel (noAF) gives a score of 0.48, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change (PP3 met). 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 (v1.2) (PM2_Supporting, PP3, PS3).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Variant & gene context
- Gene
- BRCA1
- Protein
- p.Tyr1853Asn
- Coding
- c.5557T>A
- MANE Select
- NM_007294
- dbSNP
- rs2050860958
- Type
- single nucleotide variant
- Location
- chr17:43045713 (GRCh38)
- Gene constraint
- LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 41.99 · 33 PDB
- Residue 1853
- a UniProt-annotated variant site (in fancs); the brct 2 domain; an α-helix
Similar variants
- BRCA1 p.Tyr1853Cys Pathogenic/Likely pathogenic ★★ same residue
- BRCA1 p.Tyr1853His Likely pathogenic ★ same residue
- BRCA1 p.Tyr1853Ter Pathogenic ★★★ same residue
- BRCA1 p.Tyr1853Ser Likely pathogenic ★ same residue
- BRCA1 p.Tyr1853Phe 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
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-tyr1853asn (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown