PVS1 at moderate strength: NM_001259.8:c.880_955delins is a frameshift variant predicted to result in p.(Ala294SerfsTer31), truncating the C-terminal kinase domain of CDK6. CDK6 loss of function is an established germline disease mechanism. Nonsense-mediated decay is not predicted because the variant is in the last exon (8/8) and the premature termination codon (codon 325) lies within 50 nucleotides of the final exon-exon junction. Under PMC6185798 guidance for truncating variants escaping NMD that affect a critical functional domain, PVS1 is downgraded to moderate.¹ PM2 at moderate strength: The variant is absent from gnomAD v2.1 (141,456 individuals), gnomAD v4.1 (807,162 individuals), and gnomAD-Canada v1.0 (HostSeq genomes). No population frequency data supports benign standing variation.² The variant is absent from ClinVar and COSMIC. No publications, functional data, or family segregation data were identified for this specific variant. Per the generic ACMG/AMP 2015 classification framework (PMID:25741868), PVS1 at moderate plus PM2 at moderate yields two moderate pathogenic criteria, which does not reach the threshold for Likely Pathogenic (requires ≥3 moderate or 1 strong + 1-2 moderate). This variant is classified as a Variant of Uncertain Significance (VUS).³