PS1
Not met: no established pathogenic variant shares this p.Arg797His change - the only ClinVar record carrying it is Benign across 13 submissions.
PS2
Not assessed: no proband or parental genotypes exist in the record, so de novo status cannot be tested.
PS3
Not assessed: no functional assay of MLH3 p.Arg797His was found; OncoKB reports no variant-specific functional evidence for this variant.
PS4
Not met: no case-control or case-enrichment evidence exists, and gnomAD v4.1 grpmax AF 0.0647 (174 homozygotes) precludes enrichment in affected cases.
PM1
Not met: residue 797 lies outside MLH3's annotated ATPase (~1-349) and C-terminal MutL (~1189-1403) domains, is not a significant hotspot, and carries benign variation up to 6.61% popmax.
PM2
Not met: the allele is present at 0.35% overall in gnomAD v4.1 and 6.6% in African ancestry, far above the <=0.0001 PM2 threshold.
PM3
Not met: no pathogenic MLH3 variant in trans is reported, and this common allele (gnomAD v2.1 AF 0.64%, 72 homozygotes) is tolerated biallelically.
PM5
Not met: the other missense variants at codon 797 are uncertain or likely benign (p.Arg797Cys: 2 VUS + 1 likely benign; p.Arg797Asp: VUS), with none pathogenic.
PM6
Not assessed: no proband and no assumed-de-novo observation were recorded, despite 174 homozygotes in gnomAD.
PP1
Not assessed: no pedigree or relative genotypes exist, leaving zero informative meioses for a segregation test.
PP2
Not met: MLH3 is missense-tolerant (gnomAD v2.1 mis_z 0.74, oe_mis 0.92) and missense is not an established mechanism (1 of 2,176 ClinVar missense variants P/LP).
PP3
Not met: REVEL 0.083 is far below the >=0.644 supporting PP3 threshold for this missense variant.
PP4
Not assessed: the case supplies no proband phenotype or family history, and MLH3 is absent from the MMR gene sets that define a specific phenotype (PMID:34043773).
PP5
Not met: ClinVar VCV000314383 has 13 submissions from clinical laboratories and zero expert-panel classifications, none asserting pathogenic, so PP5's expert-panel prerequisite is absent.
