NM_007194.4:c.1513T>A (p.Ser505Thr) is a missense variant in exon 14 of CHEK2, a gene associated with autosomal dominant hereditary breast, ovarian, pancreatic, and prostate cancer predisposition.¹ This variant is present at very low frequency in gnomAD: 17/233,642 alleles in v2.1 (AF=0.00728%) and 44/1,595,378 alleles in v4.1 (AF=0.00276%), with the highest subpopulation frequency of 0.083% in East Asians, all below the 0.1% PM2 threshold (PM2_Supporting).² Multiple in silico tools unanimously predict a benign effect: REVEL score 0.018 (benign range), BayesDel score -0.428 (benign range), and SpliceAI max delta 0.00 (no predicted splice impact) (BP4_Supporting).³ PVS1 is not applicable as this is a missense variant, not a null variant. PS1 and PM5 are not applicable as no same-residue pathogenic comparators have been identified. BP7 is not applicable as the variant is not synonymous.⁴ ClinVar consensus is Likely benign from four clinical laboratories, with one additional submitter reporting Uncertain significance and one reporting likely benign. No expert panel classification is available, and no reputable source has classified this variant as pathogenic.⁵ Functional evidence (PS3/BS3) remains unassessed pending full-text review of PMID:30851065 (Delimitsou et al. 2019), which performed functional characterization of CHEK2 variants in a yeast system and may include p.Ser505Thr.⁶ No de novo reports (PS2/PM6), no case-control enrichment data (PS4), no co-segregation data (PP1), and no trans-observation with a pathogenic variant (BP2) are available for this variant. Applying generic ACMG/AMP 2015 combination rules (PMID:25741868) with PM2_Supporting (1 pathogenic point) and BP4_Supporting (1 benign point), the variant is classified as a Variant of Uncertain Significance (VUS), with the benign and pathogenic evidence effectively balancing each other. The CSPEC CHEK2 VCEP v1.0.0 (doc 522546466) did not provide machine-interpretable criteria beyond the raw ruleset.⁷