Clinical Consequences of Cancer-related RAS Signaling Pathway Beyond Malignancy

Aim: Mosaic variants in oncogenic signaling pathways, particularly the Rat Sarcoma/Mitogen-Activated Protein Kinase (RAS/MAPK) cascade, are increasingly recognized causes of non-malignant developmental disorders presenting with segmental cutaneous manifestations.Methods: We evaluated patients carrying somatic mosaic variants in the Kirsten RAS Viral Oncogene Homolog, Neurofibromin 1, Fibroblast Growth Factor Receptor 3, and Neuroblastoma RAS Viral Oncogene Homolog genes.Molecular analyses were performed with emphasis on tissue-specific sequencing to detect low-level mosaicism. Results:The reported cases demonstrate the broad phenotypic spectrum of mosaic RAS/MAPK-related disorders.Clinical severity was shown to depend on both the type of variant and the extent of mosaic distribution.Importantly, several low-frequency variants were detectable only in affected tissue, highlighting the diagnostic value of tissue-specific molecular testing.Conclusion: Current American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for germline and cancerassociated variants are insufficient to classify somatic mosaic variants underlying cutaneous disorders.Our findings emphasize the need to reshape diagnostic approaches and variant classification strategies for mosaic RAS/MAPK-related dermatologic conditions.