NM_000251.2:c.366+1G>A is a canonical +1 splice donor variant in MSH2 exon 2. Exon 2 skipping is predicted to disrupt the reading frame (155 bp, not divisible by 3) and trigger nonsense-mediated decay, qualifying for PVS1 at very_strong strength under InSiGHT MSH2 VCEP v2.0.¹ The variant is absent from all queried population databases (gnomAD v2.1, v4.1, and gnomAD-Canada v1.0), meeting PM2_Supporting under the VCEP threshold of <0.00002 allele frequency.² The same genomic position with a different nucleotide change (g.47408556G>C, equivalent to c.366+1G>C) was classified as Pathogenic by the InSiGHT VCEP pilot with PVS1 and PM2_Supporting, providing strong precedent for the pathogenicity of splice disruption at this position.³ The variant has been reported in ClinVar as Pathogenic by 6 clinical laboratories and Likely Pathogenic by 2 laboratories (ClinVar ID 245947). It has been observed in COSMIC in 3 somatic cancer specimens (COSV51878772).⁴ No literature evidence was found mentioning the exact variant (c.366+1G>A). Thirteen publications were triaged and reviewed; none contained variant-specific clinical, functional, segregation, or de novo data. Applying InSiGHT MSH2 VCEP v2.0 classification rules: PVS1 (very_strong) + PM2_Supporting (supporting) meets Rule 4 (1 Very Strong + ≥2 Supporting = Pathogenic) or Rule 1 (1 Very Strong = Pathogenic). The overall classification is Pathogenic.⁵