NM_000251.3:c.1316_1318del is an in-frame deletion of 3 nucleotides in exon 8 of MSH2, resulting in p.Pro439del. This variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the InSiGHT MSH2 VCEP v2.0.0 PM2_Supporting criterion.¹ The InSiGHT MSH2 VCEP v2.0.0 declares multiple criteria as not applicable for MMR gene classification: PM1 (no recognized mutational hotspots), PM4 (protein length change from in-frame variants not used), PS4 (IHC data preferred over proband counting), PP5, BP6, BP1, BP2, BP3, PM6, and PP2.² PVS1 is not applicable to this in-frame deletion under VCEP rules as it does not introduce a premature termination codon, does not involve canonical splice sites, and no patient mRNA assay data is available. PS1 and PM5 are not applicable as they are defined for missense substitutions only.³ PP3 and BP4 are not applicable to this in-frame deletion under VCEP rules, which specify HCI prior thresholds for missense variants and SpliceAI thresholds for intronic/synonymous variants. SpliceAI predicts no splicing impact (max delta = 0.01), consistent with the variant's location within exon 8 and its in-frame nature.⁴ No functional assay data (PS3/BS3), segregation data (PP1/BS4), tumor phenotype data (PP4/BP5), de novo reports (PS2), or trans co-occurrence data (BS2) are available for this variant. The ClinVar entry (Variation ID 90623) reports classifications of Uncertain significance by 4 clinical laboratories and Likely pathogenic by 2 laboratories, with review status 'criteria provided, single submitter' at the star-level aggregate.⁵ Eight publications were reviewed for this variant, including full-text analysis where available. None of the reviewed publications mention NM_000251.3:c.1316_1318del specifically. The publications include methodological papers (SIFT Indel), ACMG/AMP guideline documents, Lynch syndrome management guidelines, and hereditary cancer syndrome reviews.⁶ Based on the InSiGHT MSH2 VCEP v2.0.0 framework, the only applicable criterion met is PM2_Supporting (absent from gnomAD). With a single supporting pathogenic criterion and no benign criteria, the evidence is insufficient for classification beyond Variant of Uncertain Significance per the VCEP combination rules. Additional evidence from tumor studies, segregation analysis, or functional assays would be required to reach a more definitive classification.⁷