BRCA2 p.Arg2287Ter
c.6859A>T · rs876661261 · VCV575178
ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP
Pathogenic for BRCA2-related cancer predisposition. Applied ACMG criteria (verbatim):
PVS1 PS3
Curation rationale (ClinGen, verbatim)
The c.6859A>T variant in BRCA2 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual arginine at amino acid 2287 (p.(Arg2287Ter)). This variant is present in gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). Nonsense of exon 12 variant predicted to cause a premature stop codon in biologically-relevant-exon 12/27 leading to nonsense mediated decay (PVS1 met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID:32046981) (PS3 met). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PS3).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | nonsense (stop-gain) | predicted loss-of-function in a haploinsufficient gene (ClinGen) |
|---|---|---|
| NMD | predicted | premature termination codon in exon 12 of 27 |
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Pangolin | Δ0.37 | loss · gain 0.01 · not in the SpliceAI release · independent |
| Constraint at this position | ||
| Conservation | phyloP 5.6 | GERP -0.31, phastCons 1 |
| Overall | ||
| CADD | 39.0 | PHRED · no single calibrated threshold — expert panels disagree |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- BRCA2
- Protein
- p.Arg2287Ter
- Coding
- c.6859A>T
- MANE Select
- NM_000059
- dbSNP
- rs876661261
- Type
- single nucleotide variant
- Location
- chr13:32344575 (GRCh38)
- Gene constraint
- LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Residue 2287
- the 'interaction with hsf2bp' region
Similar variants
- BRCA2 p.Arg2287Gly Uncertain significance ★★ ⚠ same residue
- BRCA2 p.Arg2287= Likely benign ★★ same residue
- BRCA2 p.Arg2287Ile Uncertain significance ★ ⚠ same residue
- BRCA2 p.Arg2287Ser Uncertain significance ★ same residue
- BRCA2 p.Arg2287fs 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-arg2287ter (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown