PTEN is an obligate haplo-insufficient tumor suppressor gene and is mutated in a large number of cancers. It encodes a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/mTOR signaling pathway. PTEN mutations are loss-of-function mutations and occur in 3% of urothelial carcinomas. The above variants (R130Q and G165R) are predicted to result in loss of function based on preclinical in vitro studies. Whether PTEN alterations predict for responsiveness to mTORC1 inhibitors is less certain at this time.