Isolated

NRAS and KRAS mutations, commonly identified alongside ancestral co-mutations, are generally regarded as pathogenic in adults presenting with monocytosis and/or cytopenia(s). However, their significance in isolation is not well defined. We studied a multi-institutional cohort of 52 patients with isolated RAS mutations and found that 26 (50%) did not meet diagnostic criteria for a myeloid neoplasm. Compared to patients with typical chronic myelomonocytic leukemia/myelodysplastic syndrome, these patients exhibited distinctive clinical features, including a younger age (65 years; range, 29-92 years), female predominance (60%), frequent immune-related disorders (39%), and splenomegaly (65%). Mutations predominantly involved KRAS (92%), with 87% affecting codons G12 or G13, and typically occurred at high variant allele frequency (39.0%; range, 2.6-53.0%). In three flow-sorted samples, KRAS/NRAS mutations were detected not only in granulocytes and monocytes but also in lymphocytes, reminiscent of pediatric RASopathies. A subset of patients (7/26, 27%) progressed to develop a myeloid malignancy, with acquisition of additional genetic alterations or the development of dysplasia. These findings challenge the assumption that isolated RAS mutations are sufficient to diagnose myeloid neoplasms. Instead, some cases may reflect adult-onset RASopathies or early clonal proliferations with distinct biological behavior. Recognition of such cases warrants refinement of diagnostic criteria and may influence therapeutic decision-making.