The six patients displaying a deficient MMR (dMMR) tumor phenotype (positive MSI/IHC findings) without a detectable germline pathogenic variant (PV) represent the clinical challenge of ‘Lynch-like Syndrome.’ These findings warrant extended genetic investigation for alternative causes, most notably acquired somatic hypermethylation (epimutation) of the MLH1 promoter in cases of MLH1/PMS2 loss, or the presence of PVs in less common MMR genes or in intronic/deep regulatory regions not covered by current molecular methods. The gene discussed is PMS2; the disease is neoplasm.