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 v1.0.¹ 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).² 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.³ 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).⁴ 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 BP5.⁵ 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.⁶ 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.⁷