NM_000059.4:c.8183T>C (p.Val2728Ala) is a missense variant in exon 18 of BRCA2, located within the DNA binding domain (aa 2481-3186).

This variant is present at extremely low frequency in population databases: gnomAD v2.1 (1/31,400 alleles, exclusively in genomes; exome not covered) and gnomAD v4.1 (4/1,614,072 alleles, grpmax FAF=1.746e-05). It is absent from gnomAD-Canada v1.0.

In ClinVar (Variation ID 141399), this variant is classified as Uncertain Significance by seven clinical laboratories and Likely Benign by one laboratory (criteria provided, single submitter).

ENIGMA Specifications Table 9 assigns BS3_Strong based on a calibrated functional study (Richardson et al. 2021, PMID:33609447) demonstrating that V2728A exhibits HDR activity similar to benign control variants.

ENIGMA BP4_Supporting is met: the variant is inside the DNA binding domain with no predicted impact via protein change (BayesDel no-AF=0.103, ≤0.18) and no predicted splicing impact (SpliceAI max delta=0.01, ≤0.1).

The clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is LR=1.24 based on 1 proband, falling in the neutral zone and providing no evidence for PP4 or BP5.

No pathogenic comparator exists at residue Val2728 (c.8182G>A p.Val2728Ile is classified as benign by ENIGMA), so PS1 is not met. PVS1, PM5, and other null-variant criteria are not applicable to this missense substitution.

Applying ENIGMA Table 3 combination rules: BS3_Strong (1 Strong Benign) + BP4_Supporting (1 Supporting Benign) meets the likely benign rule [1 Strong (Benign) + 1 Supporting (Benign)]. The total benign evidence is one Strong and one Supporting criterion with no pathogenic criteria met.