The PTPN11gene encodes SHP-2, a widely expressed cytoplasmic protein tyrosine phosphatase. SHP-2 is essential for activation of the RAS/MAPK signaling cascade. Most mutations are gain-of-function and result in prolonged ligand-dependent activation of the RAS/MAPK cascade. Germ-line PTPN11 mutations cause Noonan syndrome, a developmental disorder characterized by an increased risk of malignancies. Activating somatic mutations in PTPN11 have been documented in certain hematologic malignancies but they are infrequent in solid tumors. Approximately 2% of colonic adenocarcinomas harbor somatic mutations in the PTPN11 gene. The E76K variant of PTPN11 has been found to be oncogenic in gliomas, but their prognostic and therapeutic significance in colonic adenocarcinomas remains to be fully elucidated (https://oncokb.org/#/gene/PTPN11/alteration/E76K).