PTEN is 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. PTEN mutations have been reported in ~2% of head and neck squamous cell carcinomas and 15% of anaplastic thyroid carcinomas. Germline mutations of PTEN lead to inherited hamartoma and Cowden syndrome. This particular variant M134I has been reported as a likely pathogenic germline variant (ClinVar, https://preview.ncbi.nlm.nih.gov/clinvar/variation/428267/) and has also been reported as a somatic variant. Clinical trials using PI3K-beta inhibitor are available for patients with PTEN-deficient tumors.