BRCA2 p.Asn3124Lys
c.9372C>A · rs1420566833 · VCV462524
ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP
Uncertain Significance for BRCA2-related cancer predisposition. Applied ACMG criteria (verbatim):
PM2_Supporting PS3 BP4
Curation rationale (ClinGen, verbatim)
The c.9372C>A variant in BRCA2 is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 3124 (p.(Asn3124Lys)). 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 two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 39779857) (PS3 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.0006, which is below the recommended threshold of 0.18 for predicting no impact on BRCA2 via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (BP4 met). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, BP4).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9595 | likely pathogenic · top 1% in BRCA2 |
|---|---|---|
| REVEL | 0.68 | 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 1.8 | GERP -1.4, phastCons 1 |
| Regional constraint | o/e 0.87 | unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic |
| Overall | ||
| CADD | 22.8 | 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
- BRCA2
- Protein
- p.Asn3124Lys
- Coding
- c.9372C>A
- MANE Select
- NM_000059
- dbSNP
- rs1420566833
- Type
- single nucleotide variant
- Location
- chr13:32394804 (GRCh38)
- Gene constraint
- LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Residue 3124
- a UniProt-annotated variant site (in bc; pathogenic; reduced homology-directed repair activity)
Disease context
BRCA2-related cancer predisposition — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: hereditary breast ovarian cancer syndromebreast-ovarian cancer, familial, susceptibility to, 2hereditary neoplastic syndromehereditary breast carcinoma
Similar variants
- BRCA2 p.Asn3124Ile Pathogenic ★★★ same residue
- BRCA2 p.Asn3124Ser Uncertain significance ★★ ⚠ same residue
- BRCA2 p.Asn3124= Likely benign ★ same residue
- BRCA2 p.Asn3124His Likely benign ★ ⚠ same residue
- BRCA2 p.Asn3124_Trp3127del Pathogenic ★ same residue
- BRCA2 p.Asn3124fs Pathogenic ★ same residue
- BRCA2 c.316+1G>T Pathogenic ★★★ same condition
- BRCA2 c.316+2T>C 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-asn3124lys (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown