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. Most PTEN mutations are loss-of-function mutations. Mono-allelic or bi-allelic loss of PTEN is found in a considerable fraction of tumors, including gliomas (75%). In glioblastoma, PTEN loss/deletion is associated with poor patient prognosis, and/or shorter disease-free survival. The PTEN P169H mutation, however, is not definitively known to cause a loss-of-function change in the PTEN protein and has been shown to confer a phosphatase activity similar to wild-type PTEN in yeast. This variant has been identified in one case of glioblastoma according to the literature. This result should be interpreted in the clinicopathologic context.