Strikingly, the most frequently occurring SHP2 cancer mutation, a potent E76K substitution also found in Noonan’s syndrome, favors an open conformation that allows free access of substrates to the active site, in contrast to the autoinhibited conformation favored by SHP2WT in its basal state, providing a structural framework for understanding how this class of gain-of-function mutants, associated with diseases such as Noonan’s syndrome and cancer, lead to increased phosphatase activity. This evidence concerns the gene PTPN11 and cancer.