Germline RRAS2 mutations are not associated with Noonan syndrome

Prior work has demonstrated that expression of mutant forms of RRAS2 enhance guanosine triphosphate (GTP) binding of the protein and causes cellular transformation in NIH3T3 cells similar to other Ras isoforms. 4 However, in contrast to other Ras family members, RRAS2 appears to exert its function through RAF1-independent signalling pathways and likely signals through other pathways, including PI3K, AKT, RAC and JNK. 4 5 JMML is a myeloproliferative disorder that affects young children and is treated with stem cell transplantation. 6 The most common driver mutations in this disease include NF1, NRAS, KRAS, PTPN11, CBL and RRAS and are detected in 90% of all patients. 2 While RRAS2 mutations have been limited to solid tumours to date, 7 we identified an RRAS2 p.Q72L mutation in two patients with JMML, neither of whom harboured other Ras pathway driver mutations.