NM_001259.8:c.197G>A (p.Arg66Lys) is a missense variant in CDK6, a cyclin-dependent kinase with established oncogenic roles in cancer.¹ This variant is extremely rare, observed in only 1 of 1,606,862 alleles (AF=6.22×10⁻⁷) in gnomAD v4.1, and absent from gnomAD v2.1 and gnomAD-Canada v1.0, meeting PM2 at supporting level.² Multiple in silico predictors do not support a deleterious effect: REVEL score is 0.192 (benign-leaning), BayesDel score is −0.083 (benign), and SpliceAI predicts no splicing impact (max delta=0.00), meeting BP4 at supporting benign level.³ This variant is absent from ClinVar and has not been reported in the literature. No functional data, segregation data, de novo reports, or case-control studies are available.⁴ The variant does not lie in a statistically significant mutational hotspot per cancerhotspots.org, and no pathogenic missense variant at the same residue (Arg66) has been identified.⁵ PVS1 is not applicable as this is a missense variant, not a null variant; BP1 is not applicable as CDK6 is an oncogene whose primary disease mechanism is gain-of-function rather than truncating loss-of-function.⁶ Overall, one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met. These criteria are in equipoise, resulting in a classification of Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 generic combination rules.⁷