NM_032043.3:c.143C>A (p.Thr48Lys) is a missense variant in BRIP1, a moderate-penetrance breast and ovarian cancer predisposition gene where the predominant disease mechanism is protein truncation.¹ This variant is extremely rare in population databases: gnomAD v2.1 allele frequency is 0.00319% (1/31,388 alleles) and v4.1 allele frequency is 0.00037% (6/1,613,830 alleles) with no homozygotes observed, meeting PM2 at supporting strength.² In silico analysis supports a deleterious effect: REVEL score of 0.728 exceeds the 0.7 threshold for damaging prediction; the Thr48Lys substitution is non-conservative, replacing a polar uncharged residue with a positively charged one, meeting PP3 at supporting strength.³ BRIP1 disease-causing mutations predominantly result in protein truncation or nonsense-mediated RNA decay. This missense variant is not consistent with the primary disease mechanism, meeting BP1 at supporting benign strength.⁴ This variant has been reported in ClinVar as Uncertain significance by 5 clinical laboratories (Variation ID 234642, 1-star review status). No functional studies, segregation data, de novo observations, or case-control data are available.⁵ No functional studies or literature directly testing NM_032043.3:c.143C>A (p.Thr48Lys) or a systematically characterized residue range including position 48 were identified. The variant has not been reported in COSMIC and OncoKB reports Unknown Oncogenic Effect.⁶ The evidence profile includes one pathogenic supporting criterion (PM2), one pathogenic supporting criterion (PP3), and one benign supporting criterion (BP1), resulting in net neutral evidence. Based on generic ACMG/AMP 2015 combination rules, this variant is classified as a Variant of Uncertain Significance.⁷