This is the first case of an endometrial carcinoma harboring a somaticPOLE exonuclease mutation related to an ultra-mutator phenotypeacting as a ‘second hit’ in association with a germline truncating mutation of the gene.Germline heterozygous missense mutations affecting the POLE exonucleasedomain are associated with a syndrome called Polymerase Proofreading-AssociatedPolyposis (PPAP) that increases the risk for the development of multiple colorectaladenomas and colorectal cancer (Briggs etal., 2013). This evidence concerns the gene POLE and colorectal cancer.