In addition to the hypothesis regarding possible “cryptic” deleterious germline variants in MMR genes, there are two other possible explanations proposed: unknown germline pathogenic or likely pathogenic variants affecting other than MMR genes may drive the tumor towards MSI (as it has been recently described for MUTYH and POLE genes in isolated LLS cases [10,11,12]), and biallelic somatic inactivation of an MMR gene in LLS tumors may cause MMRd (as it has been suggested in several reports [13,14,15,16]). The gene discussed is POLE; the disease is neoplasm.