PM2 (supporting): The NM_032043.3:c.476A>C (p.Lys159Thr) missense variant in BRIP1 is absent from all large population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting level in the generic ACMG/AMP 2015 framework.¹ BP1 (supporting benign): BRIP1 is a gene for which loss of function is the established disease mechanism. Truncating variants represent the primary pathogenic spectrum. This missense variant is not a predicted null variant, applying BP1 at supporting benign level.² BP4 (supporting benign): Multiple computational predictors (REVEL 0.311, BayesDel 0.027, SpliceAI max delta 0.05) converge on a benign prediction with no evidence of splicing disruption, meeting BP4 at supporting benign level.³ The variant has one supporting pathogenic criterion (PM2) and two supporting benign criteria (BP1, BP4). Per ACMG/AMP 2015 combination rules, criteria at the supporting level in opposing directions do not sum to a definitive classification, and the variant is classified as a variant of uncertain significance (VUS).⁴