POLE and cancer: Moreover, there are some other genes, such as RPS20, POLE, POLD1, AXIN2, NTHL1, MSH3, RNF43 and GREM1, that are classified as moderate or low penetrance genes for the risk of CRC (Table 1); however, the increasing evidence of associated cancer risks suggest that they should be analyzed, whenever possible, in patients with a suspected CRC predisposition, especially the ones who have tested negative for the other syndromes.