POLE and neoplasm: In this situation, if the mutational signature analysis does not reveal any of the POLE/D1-associated signatures, i.e., signatures 14 or 20 when the germline variant affects the ED of POLE or ED respectively, it is highly advisable to analyze a second tumor, ideally MMR proficient, developed in the same family or harboring the same variant but in a somatic context, verifying that no other somatic ED variant is present.