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 p.Y68H is a reported pathogenic variant that causes tyrosine to histidine substitution at codon 68 affecting NH2-terminal phosphatase domain. This variant has been reported previously in association with PTEN-related disorders. Functional studies demonstrate that individuals harboring this variant have decreased levels of the PTEN protein when compared to wild type controls. However, its clinical significance remains to be fully elucidated.