BRCA2 p.Glu3309Ter
c.9925G>T · rs80359251 · VCV52919
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 | escapes | premature termination codon in the last exon (27 of 27) — the truncated protein is likely expressed. PVS1 input, not an applied code |
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 1 | GERP 0.59, phastCons 0.31 |
| Overall | ||
| CADD | 36.0 | PHRED · no single calibrated threshold — expert panels disagree |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
gnomAD v4.1 · exomes + genomesRarity 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.
ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP
Uncertain Significance for BRCA2-related cancer predisposition. Applied ACMG criteria (verbatim):
PM2_Supporting
Curation rationale (ClinGen, verbatim)
The c.9925G>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 Glutamic acid at amino acid 3309 (p.Glu3309Ter). 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). Nonsense variant predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, and lead to truncation of a region with unknown protein function (sequence up to BRCA2:p.Glu3309 is maintained) (PVS1 not met). Reported by two calibrated studies with discordant results. Exhibits protein function similar to benign control variants (PMID: 29988080) and pathogenic control variants (PMID: 18607349) (PS3 and BS3 not 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).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Variant & gene context
- Gene
- BRCA2
- Protein
- p.Glu3309Ter
- Coding
- c.9925G>T
- MANE Select
- NM_000059
- dbSNP
- rs80359251
- Type
- single nucleotide variant
- Location
- chr13:32398438 (GRCh38)
- Gene constraint
- LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Residue 3309
- the 'tr2 region' region
Similar variants
- BRCA2 p.Glu3309Gly Uncertain significance ★★ ⚠ same residue
- BRCA2 p.Glu3309Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
- BRCA2 p.Glu3309Val Conflicting classifications of pathogenicity ★ ⚠ same residue
- BRCA2 p.Glu3309Leu Uncertain significance ★ 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
- BRCA2 c.316+5G>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-glu3309ter (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown