BRCA2 p.Asp2723Ala
c.8168A>C · rs41293513 · VCV52516
ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP
Pathogenic for BRCA2-related cancer predisposition. Applied ACMG criteria (verbatim):
PP1_Strong PS3 PP3
Curation rationale (ClinGen, verbatim)
The c.8168A>C variant in BRCA2 is a missense variant predicted to cause substitution of Aspartic acid by Alanine at amino acid 2723 (p.Asp2723Ala). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or 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). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.576, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. SpliceAI predictor score of 0.00 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 33609447, 33293522) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.557 (based on Pathology LR=0.214; Co-occurrence LR=1.102; Family History LR=2.36), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; 31853058, Internal lab contributors). Cosegregation analysis of family(ies) carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 74321.3, above the thresholds for Very strong pathogenic evidence (LR >350) (PP1_Very strong; Internal lab contributors). In summary, this variant meets the criteria to be classified as a Pathogenic variant variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PP3, PS3, PP1_Very strong).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9713 | likely pathogenic ✓ concordant with ClinVar · top 1% in BRCA2 |
|---|---|---|
| REVEL | 0.94 | strongly pathogenic-leaning |
| ⇒ AlphaMissense and REVEL both call this damaging. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · A>G here scores Δ0.23 · evaluated, not missing |
| 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 | 26.3 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
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.Asp2723Ala
- Coding
- c.8168A>C
- MANE Select
- NM_000059
- dbSNP
- rs41293513
- Type
- single nucleotide variant
- Location
- chr13:32363370 (GRCh38)
- Gene constraint
- LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Residue 2723
- a UniProt-annotated variant site (in bc; pathogenic; major splicing aberration identified with this mutant; reduced homology-directed repair activity); a UniProt-annotated variant site (in bc; pathogenic; disrupts interaction with sem1 promoting interaction with xpo1 and brca2 cytoplasmic localization; in heterozygous state promotes rad51 cytoplasmic localization; reduced homology-directed repair activity); the 'interaction with sem1' region
Similar variants
- BRCA2 p.Asp2723Gly Pathogenic ★★★ same residue
- BRCA2 p.Asp2723His Pathogenic ★★★ same residue
- BRCA2 p.Asp2723Val Pathogenic/Likely pathogenic ★★ same residue
- BRCA2 p.Asp2723= Likely benign ★★ same residue
- BRCA2 p.Asp2723Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
- BRCA2 p.Asp2723Glu Conflicting classifications of pathogenicity ★ ⚠ 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-asp2723ala (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown