PS1
Not met: p.Lys508Glu is not established as pathogenic - ClinVar shows 5 Likely benign and 1 VUS submission and no pathogenic assertion.
PS2
Not assessed: no parental-testing data exist, so the confirmed de novo PS2 requires (PMID:25741868) is undeterminable; gnomAD v2.1 shows 106 alleles and v4.1 two homozygotes.
PS3
Not met: no assay has tested p.(Lys508Glu), and OncoKB reports no variant-specific functional evidence for this change.
PS4
Not met: no case-control enrichment exists, as the variant is absent from the 1231-case CRC cohort and present in gnomAD v4.1 at 392/1,612,578 alleles.
PM1
Not met: residue 508 lies in MSH3 MutS domain II but is no hotspot and is not free of benign variation (gnomAD popmax AF 0.44%, 2 homozygotes).
PM2
Not met: total allele frequency 0.024-0.038% in gnomAD v4.1/v2.1 exceeds the 0.01% PM2 rarity threshold, with the African/African American popmax at 0.44%.
PM3
Not met: no pathogenic variant was observed in trans with MSH3 c.1522A>G, and no phase-resolved proband data supports an in-trans configuration.
PM5
Not met: the only other codon-508 missense variant, p.Lys508Arg, has conflicting ClinVar classifications and is not established pathogenic.
PM6
Not assessed: no parental testing or de novo observation is documented, so PM6's assumed-de-novo premise (PMID:25741868) cannot be evaluated; the variant recurs in gnomAD (106 v2.1 alleles).
PP1
Not assessed: no pedigree or relative genotypes exist and no paper reports this variant in a family, so PP1 co-segregation (PMID:25741868) cannot be evaluated.
PP2
Not met: MSH3 shows no missense constraint (gnomAD oe_mis 1.08, mis_z -1.29) and its established pathogenic variants are truncating, not missense.
PP3
Not met: REVEL 0.191 for this missense variant is below the >=0.644 PP3 supporting threshold.
PP4
Not assessed: no proband phenotype or family history was recorded for this case, so PP4's requirement for a highly specific single-gene disease phenotype cannot be tested.
