NM_032043.3:c.254C>T (p.Ser85Leu) is a missense variant in BRIP1. PVS1 does not apply as this is not a null variant.¹ This variant is present at extremely low frequency in population databases: gnomAD v2.1 at 0.00119% (3/251,440 alleles) and gnomAD v4.1 at 0.00099% (16/1,613,990 alleles), with no homozygotes observed. This meets the PM2 criterion at supporting strength for a rare variant in a gene associated with dominant cancer predisposition.² Multiple in silico prediction tools support a benign effect: REVEL score 0.078 (strongly benign-leaning), BayesDel score -0.316 (benign), and SpliceAI max delta 0.03 (no predicted splicing impact). These concordant predictions meet BP4 at supporting benign strength.³ No functional studies have directly tested p.Ser85Leu. The largest BRIP1 missense functional characterization study (PMID:31822495) tested 20 helicase domain variants but did not include this residue. OncoKB reports no variant-specific functional evidence.⁴ ClinVar classifies this variant as Uncertain Significance (Variation ID: 141545) with 1-star review status based on 14 clinical laboratory submissions. No expert panel classification is available. This does not meet criteria for PP5 or BP6 application.⁵ No case-control studies, cosegregation data, de novo reports, or same-residue pathogenic comparators are available. BRIP1 missense variants in the helicase domain are a known disease mechanism (PMID:31822495), so BP1 does not apply despite this being a missense change.⁶ The combined evidence (PM2 supporting + BP4 supporting benign) yields conflicting benign and pathogenic signals. The overall classification is Variant of Uncertain Significance (VUS), consistent with the ClinVar consensus.⁷