The detection of GNAQ, GNA11, PLCB4, and CYSLTR2, as well as the methylation profiling, can support the diagnosis of these tumors as primary CNS neoplasms, and discriminate them from other melanocytic lesions, including brain or leptomeningeal metastases from melanoma, where nearly 50% of cases harbor HRAS, KRAS, BRAF, or KIT mutations. This evidence concerns the gene PLCB4 and central nervous system neoplasm.