Although germline variants in POLE and polymerase δ (POLD) have been associated with germline variants in mismatch repair genes resulting in MSI tumors (i.e., Lynch Syndrome), somatic mutations in POLE have been detected in 1% of all colorectal cancers and occur only in MSS colorectal cancer (i.e., mutually exclusive of MSI status) [14,15,16]. This evidence concerns the gene POLE and Lynch syndrome.