|Amino Acid Change||G165R|
|DNA Change (Coding Nucleotide)||493G>A|
|Transcript ID (GRCh37/hg19)||ENST00000371953|
|Genomic Coordinates (GRCh37/hg19)||10:89711875-89711875|
|Tumor Type||Primary Site|
PTEN is a tumor suppressor gene, located on chromosome 10q23. It encodes a lipid and protein phosphatase that negatively regulates the PI3K/AKT/mTOR pathway. Cancer-associated alterations in this gene often result in loss of PTEN protein and upregulation of the PI3K/AKT/mTOR pathway. Germline mutations of PTEN lead to inherited hamartoma and Cowden syndrome while somatic mutations are also known to occur in multiple malignancies. PTEN alterations are rare and not well characterized in parathyroid tumors. One study reported loss of heterozygosity of PTEN in 7 of 14 parathyroid carcinomas. PTEN p.G165R variant is a reported pathogenic variant that causes glycine to arginine substitution at codon 165 affecting NH2-terminal phosphatase domain. This variant has been reported previously in endometrial and CNS tumors in COSMIC data base. Functional studies demonstrate that individuals harboring this variant have decreased levels of the functional PTEN protein when compared to wild type controls. However, its clinical significance remains to be fully elucidated.
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.