NM_000251.2:c.367-1G>A is a canonical splice acceptor variant (IVS2-1G>A) disrupting the invariant AG dinucleotide of intron 2 in MSH2, a gene for which loss of function is an established mechanism for Lynch syndrome.¹ SpliceAI predicts strong splice disruption with a maximum delta score of 0.99 (acceptor loss 0.99), and cDNA analysis from patient lymphocytes (Wolf et al. 2005, PMID:15926618) confirmed aberrant splicing: the variant creates a new splice acceptor 1 bp downstream, resulting in deletion of a guanine (r.367delg) and a frameshift (p.122fsX173) predicted to introduce a premature termination codon subject to nonsense-mediated decay.² Under InSiGHT MMR VCEP v2.0, canonical splice site variants at IVS+/-1 or IVS+/-2 where exon skipping or cryptic splice site use disrupts the reading frame and is predicted to undergo NMD qualify for PVS1 at very_strong strength. The premature termination codon at position 173 is well upstream of the MSH2 NMD boundary at codon 891.³ The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the VCEP PM2_Supporting threshold of <0.00002 allele frequency. It was also absent from 100 healthy control alleles in the Wolf et al. study.⁴ ClinVar classifies this variant as Likely pathogenic (Variation ID 91075), reviewed by the InSiGHT expert panel, consistent with the VCEP assessment.⁵ No benign or conflicting evidence was identified. BS3 is contradicted by the confirmed splicing aberration. BP4 is contradicted by the strong SpliceAI prediction. PP3 is not applied per VCEP rules prohibiting combination with PVS1 for canonical splice variants.⁶ Under InSiGHT MMR VCEP v2.0 combination rules (Rule 1): 1 PVS1_VeryStrong criterion is sufficient for Pathogenic classification.⁷