Much of the genetic predisposition to polyposis, and particularly to serrated polyposis (SP), remains unknown. Only germline pathogenic variants in RNF43, a tumor suppressor that exerts negative feedback in the Wnt/β-catenin signaling pathway, have been causally linked to some SP cases (<2%), a disease associated with increased risk of colorectal cancer (CRC). Most known hereditary CRC and polyposis genes affect DNA repair, BMP/TGF-b, or Wnt signaling, being the latter associated with adenomatous and serrated polyposis phenotypes. Based on this observation, we evaluated the presence and role of germline variants in those pathways in unsolved polyposis patients.