BRCA2 p.Asp189Gly
c.566A>G · rs397507359 · VCV37986
ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP
Likely Pathogenic for BRCA2-related cancer predisposition. Applied ACMG criteria (verbatim):
PVS1 PM2_Supporting
Curation rationale (ClinGen, verbatim)
The c.566A>G variant in BRCA2 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 189 (p.(Asp189Gly)). This variant is absent from gnomAD v4.1 (read depth ≥25x in >90% samples, PM2_Supporting met). This BRCA2 missense variant has a SpliceAI score of 0.7, predicting an impact on splicing (score threshold ≥0.2) (PP3 not applied because a PVS1 code is met). This variant is reported to result in aberrant mRNA splicing. Minigene, RT-PCR, and RNAseq demonstrated that the variant causes deletion of part of the exon (r.562_631del), resulting in an out-of-frame transcript. The percent aberrant transcript produced from the variant allele using allele specific assessment with sequence analysis was determined to be >90% (ENIGMA unpublished data, Ambry internal data, Internal lab contributor). Final code strength determined by the rubric: PVS1 (RNA). 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, PVS1 (RNA)).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.8813 | likely pathogenic ✓ concordant with ClinVar · top 2% in BRCA2 |
|---|---|---|
| REVEL | 0.259 | benign-leaning |
| ⇒ AlphaMissense calls this damaging; REVEL does not. | ||
| Splicing | ||
| SpliceAI | Δ0.65 | donor gain, 5 bp away · raw score · deltas |
| Pangolin | Δ0.74 | gain · loss 0.12 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 11 | GERP 2.3, phastCons 1 |
| Regional constraint | o/e 1.03 | unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic |
| Overall | ||
| CADD | 34.0 | 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.Asp189Gly
- Coding
- c.566A>G
- MANE Select
- NM_000059
- dbSNP
- rs397507359
- Type
- single nucleotide variant
- Location
- chr13:32326548 (GRCh38)
- Gene constraint
- LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Similar variants
- BRCA2 p.Asp189Asn Uncertain significance ★ ⚠ same residue
- BRCA2 p.Asp189Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
- BRCA2 p.Asp189Val Uncertain significance ★ same residue
- BRCA2 p.Asp189fs 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
- 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-asp189gly (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown