The CDK4 c.71G>T (p.Arg24Leu) missense variant is located at codon 24 within the protein kinase domain, a statistically significant mutational hotspot per cancerhotspots.org where established pathogenic gain-of-function missense variants (p.Arg24Cys, p.Arg24His) cause familial melanoma (PM1, moderate).¹ This is a novel missense change (p.Arg24Leu) at the same amino acid residue where different missense changes have been determined to be pathogenic — p.Arg24Cys and p.Arg24His are well-established pathogenic CDK4 variants associated with familial melanoma susceptibility (PM5, moderate).² The variant is absent from gnomAD-Canada v1.0; gnomAD v2.1 and v4.1 data were unavailable at the time of assessment. Absence from available population databases supports rarity below the 0.1% PM2 threshold (PM2, supporting).³ OncoKB, a curated somatic cancer knowledgebase, classifies this specific variant as Likely Oncogenic with a Likely Gain-of-function biological effect, providing a secondary citation for a deleterious functional impact at this well-characterized residue (PS3, supporting).⁴ Multiple in silico predictors yield benign scores: REVEL 0.242 (benign), BayesDel -0.0848 (benign), and SpliceAI max delta 0.00 (no splice impact). While these results favor a benign interpretation (BP4, supporting benign), they do not outweigh the pathogenic evidence from the hotspot location, same-residue pathogenic comparator variants, population absence, and curated functional annotation.⁵ Applying the generic ACMG/AMP 2015 combination rules (PMID:25741868): 2 moderate criteria (PM1, PM5) plus 2 supporting criteria (PM2, PS3) meet the threshold for Likely Pathogenic. One supporting benign criterion (BP4) is present but is insufficient to offset the pathogenic evidence.⁶