PS1
Not met: no pathogenic variant producing the same amino-acid change p.Arg1152His is established; the only ClinVar record for it is Uncertain significance.
PS2
Not assessed: no proband phenotype or parental testing results were available to evaluate a de novo origin.
PS3
Not assessed: no functional studies of this variant exist; OncoKB lists no variant-specific functional evidence for R1152H.
PS4
Not assessed: no case-control study, case series, or affected-proband allele counts for this variant were available.
PM1
Not met: the variant is not in a statistically significant mutational hotspot, and no domain annotation places residue 1152 in a critical functional domain.
PM3
Not assessed: no observation of the variant in trans with a pathogenic MLH3 variant exists; phase data are lacking.
PM5
Not assessed: no different missense change at Arg1152 with a pathogenic classification was identified to serve as the required comparator.
PM6
Not assessed: no parental testing or de novo assertion data were available.
PP1
Not assessed: no pedigree or segregation data were available to evaluate cosegregation with disease.
PP2
Not assessed: no missense-constraint data for MLH3 were available, and evidence favors loss-of-function rather than missense as the disease mechanism.
PP3
Not met: SpliceAI max delta 0.06 and REVEL 0.361 both fall below their calibrated pathogenic thresholds.
PP4
Not assessed: no confirmed proband phenotype or family history was available.
PP5
Not met: no ClinVar expert-panel (VCEP) pathogenic classification exists for this exact variant; all six submissions are Uncertain significance.
