PS1
Not met: the same change, p.(Pro681Ser), appears in the literature and ClinVar, but no source establishes it as pathogenic.
PS2
Not assessed: no proband-parent trio or parental-testing data exists for this variant in any source.
PS3
Not assessed: no functional study of this variant exists; a ClinVar submitter states none have been performed.
PS4
Not met: the single carrier in 199 cases (0.5%) does not exceed the 0.229% population frequency, so no enrichment is demonstrated.
PM1
Not met: despite a conserved ATPase-region location, 7 gnomAD v4.1 homozygotes show benign variation at this exact residue.
PM2
Not met: the highest population allele frequency (0.229% in gnomAD v4.1) exceeds the 0.1% PM2 threshold.
PM3
Not assessed: no source provides phase or second-allele data showing the variant in trans with a pathogenic MSH3 variant.
PM5
Not assessed: no alternate missense change at codon 681 with an established pathogenic classification was identified.
PM6
Not assessed: no de novo or assumed-de-novo occurrence is reported in ClinVar or the variant-bearing publications.
PP1
Not assessed: no affected relatives of any carrier have been genotyped, so co-segregation cannot be evaluated.
PP2
Not met: MSH3 is missense-tolerant (this variant has 7 gnomAD v4.1 homozygotes), and disease is loss-of-function mediated, not missense-driven.
PP3
Not met: REVEL 0.496 falls below the 0.773 PP3 supporting threshold, and SpliceAI 0.03 predicts no splice impact.
PP4
Not assessed: no documented proband phenotype or family history is available to evaluate.
PP5
Not met: ClinVar VCV000656200 has zero expert-panel submissions, and PP5 requires an exact-variant expert-panel pathogenic classification.
