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.

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.

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.

OncoKB curates this variant as Likely Oncogenic with a Likely Loss-of-function biological effect, consistent with the predicted truncating mechanism.

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.

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.