BRCA2 p.Leu3101Pro
c.9302T>C · rs28897758 · VCV216263
ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP
Likely Pathogenic for BRCA2-related cancer predisposition. Applied ACMG criteria (verbatim):
PM2_Supporting PS3 PP3 PP4
Curation rationale (ClinGen, verbatim)
The c.9302T>C variant in BRCA2 is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 3101 (p.(Leu3101Pro)). 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). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 38417439, 32444794, 39779857) (PS3 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.32, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2.19 (based on Family History LR=2.19), within the thresholds for supporting evidence towards pathogenicity (LR >2.08 & ≤4.3) (PP4 met; PMID: 31853058). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP3, PP4).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9258 | likely pathogenic ✓ concordant with ClinVar · top 1% in BRCA2 |
|---|---|---|
| REVEL | 0.788 | moderately pathogenic-leaning |
| ⇒ AlphaMissense and REVEL both call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.9 | GERP 2.5, phastCons 1 |
| Regional constraint | o/e 0.87 | unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic |
| Overall | ||
| CADD | 26.1 | 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
- BRCA2
- Protein
- p.Leu3101Pro
- Coding
- c.9302T>C
- MANE Select
- NM_000059
- dbSNP
- rs28897758
- Type
- single nucleotide variant
- Location
- chr13:32394734 (GRCh38)
- Gene constraint
- LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Residue 3101
- a UniProt-annotated variant site (in)
Similar variants
- BRCA2 p.Leu3101= Likely benign ★★★ same residue
- BRCA2 p.Leu3101Arg Pathogenic/Likely pathogenic ★★ same residue
- BRCA2 p.Leu3101Gln Uncertain significance ★★ ⚠ same residue
- BRCA2 p.Leu3101Val Conflicting classifications of pathogenicity ★ same residue
- BRCA2 p.Leu3101fs Pathogenic/Likely pathogenic ★★ same residue
- BRCA2 c.316+1G>T Pathogenic ★★★ same condition
- BRCA2 c.316+2T>C Pathogenic ★★★ same condition
- BRCA2 c.316+5G>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/brca2-p-leu3101pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown