First, presence of mutations at untested regulatory regions of the analyzed genes; second, an MMR deficiency caused by somatic biallelic inactivation; third, genetic mosaicism; fourth, germline mutations in other genes directly or indirectly involved with MMR function, such as SETD2 [39], POLE and POLD1 [40], and finally other unknown genetic or epigenetic mechanisms (Figure 1). The gene discussed is POLD1; the disease is mismatch repair cancer syndrome 1.