PVS1
Not met: PMS2 c.497T>C is a missense substitution, not a nonsense, frameshift, splice-site, initiation-codon or copy-number null, and SpliceAI max delta 0.012 excludes a splice consequence.
PS1
Not met: Leu166 is a CTN codon, so only c.497T>C itself can encode p.Leu166Pro - no alternate nucleotide change exists for PS1.
PS2
Not assessed: with no proband parental testing or tumor data, zero of the >=0.5 de novo points required for PS2_Supporting could be assigned.
PS3
Not assessed: no calibrated MMR functional assay or functional-odds result exists for c.497T>C (p.Leu166Pro), so the VCEP PS3 threshold of functional odds >2.08 cannot be evaluated.
PM2
Not met: gnomAD v4.1 total AF 0.00013713 is about 7-fold above the 0.00002 gnomAD-v4 rarity threshold.
PM3
Not assessed: the PMS2 VCEP PM3 rule requires a co-occurring pathogenic/likely pathogenic PMS2 variant in trans and a CMMRD-consistent proband, and neither is documented.
PM5
Not met: the only other missense at residue 166, p.Leu166Gln, is a single-submitter ClinVar VUS, so no VCEP-pathogenic comparator exists for PM5.
PP1
Not assessed: no pedigree or relative genotypes exist for this variant, so the combined Bayes likelihood ratio needed for PP1 (>=2.08) cannot be computed.
PP4
Not assessed: CSPEC PP4 requires tumour MSI-H and/or MMR-protein-loss data at a 1-3 tumour threshold, and no tumour phenotype data exist for this case.
PP5
Not met: ClinVar VCV000135944 has zero expert-panel submissions (1 star, conflicting single-lab classifications), so no expert-panel pathogenic assertion exists to trigger PP5.
