This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PM2 criterion at moderate strength for absence from population databases.¹ Residue Arg365 is located in a statistically significant mutational hotspot per cancerhotspots.org, meeting PM1 at supporting strength.² In silico predictions are conflicting: REVEL score 0.62 suggests a moderately damaging effect while BayesDel score 0.044 suggests a benign effect and SpliceAI predicts no splicing impact (max delta 0.00). Neither PP3 nor BP4 can be applied due to discordant predictions.³ ClinVar reports conflicting classifications for this variant: Likely pathogenic (GeneDx, 1 submitter) and Uncertain significance (Labcorp Genetics, 1 submitter), both from single clinical laboratories without expert panel review. The split classification precludes application of PP5.⁴ No variant-specific functional data are available for NM_017617.5:c.1093C>T (p.Arg365Cys). OncoKB curates this variant as Likely Oncogenic based on somatic literature, but primary publications were not available in full text for independent verification. PS3 cannot be met without experimental functional characterization.⁵ Combined ACMG evidence: PM2 (moderate) and PM1 (supporting) are met. Per generic ACMG/AMP 2015 combination rules (PMID:25741868), one moderate and one supporting criterion does not reach the threshold for Likely Pathogenic (requires ≥2 moderate plus ≥2 supporting, or ≥3 moderate, or 1 moderate plus ≥4 supporting). The overall classification is Uncertain Significance (VUS).⁶