Germline PTEN (Phosphatase and TENsin homologue deleted on chromosome TEN) mutations predispose to phenotypically diverse disorders that share several overlapping clinical features: Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, Proteus syndrome and Proteus-like syndrome, collectively classified as PTEN hamartoma tumour syndrome (PHTS). The meticulous acquisition and documentation of PHTS phenotypic data at different levels and the profiling of the plethora of genetic changes in PTEN and other genes within the same or related pathways are important in resolving the challenge of discriminating heritable cancers from sporadic PHTS-mimicking clinical features. The characterization of PTEN and PTEN-related pathways from a multidisciplinary perspective underscores the importance of incorporating data from different-omics, which is crucial for the advancement of personalized medicine.