NM_000251.3:c.609del (p.Gly204GlufsTer10) is a frameshift deletion in exon 3 of MSH2 that introduces a premature termination codon at position 214, well before the InSiGHT VCEP-defined cutoff of codon 891 for PVS1 application at Very Strong strength.¹ The variant is absent from population databases including gnomAD v2.1 and v4.1 (0 alleles across all populations), meeting the VCEP PM2_Supporting threshold of <1 in 50,000 alleles.² SpliceAI predicts no splice-altering effect (max delta score = 0.01), consistent with a frameshift deletion that exerts its effect at the protein level through premature truncation rather than aberrant splicing.³ OncoKB curates this variant as Likely Oncogenic with a Likely Loss-of-function biological effect, consistent with the predicted truncating mechanism.⁴ No benign evidence criteria (BA1, BS1, BS2, BS3, BS4, BP5) are met; the variant is absent from population databases, no functional data support benign effect, and no alternate molecular basis or negative segregation data exist.⁵ Applying the InSiGHT MSH2 VCEP v2.0.0 combining rules: PVS1_VeryStrong + PM2_Supporting yields 1 Very Strong + 1 Supporting. The VCEP rule set does not define a specific rule for this exact combination (Rule 4 requires ≥2 Supporting for Pathogenic; Rule 10 requires 1 Moderate for LP). Falling back to generic ACMG/AMP 2015 combination rules (PMID:25741868): 1 PVS1-level evidence (minimum Strong equivalent) + 1 Supporting → Likely Pathogenic. PP1 and PP4 remain unassessed; if either is met at Supporting level, the classification would upgrade to Pathogenic under VCEP Rule 4.⁶