In this cohort study of 701 patients with germline PTEN variants (PTEN hamartoma tumor syndrome, PHTS), approximately half had at least 1 cancer diagnosis, with significantly elevated lifetime risks for breast (91%), endometrial (48%), thyroid (33%), kidney (30%), and colorectal cancers (17%), as well as melanoma (5%). This evidence concerns the gene PTEN and PTEN hamartoma tumor syndrome.