PS2
Not assessed: no proband, parental testing, parentage confirmation, or family-history data exist for this variant in the case evidence.
PS3
Not met: no functional RNA/splice or protein assay exists for p.(Leu1347=); SpliceAI max delta 0.014 is in-silico and cannot support PS3.
PS4
Not met: this synonymous variant is absent from Supplementary Table S1, so its recurrence count of 0 fails the framework's combined EC count >=10 requirement.
PM1
Not met: p.Leu1347= is not one of the framework's enumerated exonuclease-domain hotspot substitutions and lies outside the exonuclease domain, whose hotspots span residues 286-459.
PM3
Not assessed: no trans/phase data - no second POLE variant or parental genotypes - so PM3's requirement for a pathogenic variant in trans cannot be evaluated.
PM6
Not assessed: no proband or parent-of-origin data exist, so no assumed de novo occurrence can be documented for this variant.
PP1
Not assessed: no pedigree, affected relatives, or meioses are available, so co-segregation of c.4039C>T with disease cannot be evaluated.
PP3
Not met: synonymous variant with SpliceAI max delta 0.014, far below the >=0.2 PP3 supporting threshold.
PP4
Not assessed: no proband phenotype or family-history data was recorded for this case, so phenotype specificity for a single-gene disorder could not be evaluated.
PP5
Not met: ClinVar classifies this variant Likely benign from 2 single-submitter laboratories with 0 expert-panel submissions, failing the expert-panel pathogenic requirement.
