NM_007194.4:c.1392G>T (p.Lys464Asn) is a missense variant in CHEK2 located in the kinase domain where pathogenic missense variants cluster.¹ This variant is extremely rare in population databases, with 1 allele in 233,756 in gnomAD v2.1 (AF=4.28e-6) and 0 alleles in 1,594,506 in gnomAD v4.1.² Multiple lines of computational evidence (REVEL=0.321, BayesDel=-0.221, SpliceAI max delta=0.27) suggest no significant impact on the gene product.³ This variant has been reported in ClinVar as Uncertain significance by 5 clinical laboratories (VariationID 530112) with no pathogenic assertion from any reputable source.⁴ PVS1 is not applicable as this is a missense change. No de novo, segregation, case-control, same-residue comparator, or confirmed functional evidence was available from verified sources to support pathogenicity.⁵ Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): PM1 (supporting) + PM2 (supporting) + BP4 (supporting benign) results in insufficient evidence to classify as pathogenic, likely pathogenic, or likely benign. The variant remains a Variant of Uncertain Significance (VUS).⁶