Melanocytic neoplasms have been genetically characterized in detail during the last decade. Recurrent exon 3 mutations have been recognized in the distinct group of melanocytic tumors showing deep penetrating nevus-like morphology. In addition, they have been identified in 1-2% of advanced melanoma. Performing a detailed genetic analysis of difficult-to-classify nevi and melanomas with mutations, we found that benign tumors (nevi) show characteristic morphological, genetic and epigenetic traits, which distinguish them from other nevi and melanoma. Malignant -mutant tumors (melanomas) demonstrated a different genetic profile, instead grouping clearly with other non- melanomas in methylation assays. To further evaluate the role of mutations in melanoma, we assessed a large cohort of clinically sequenced melanomas, identifying 38 tumors with exon 3 mutations, including recurrent S45 ( = 13, 34%), G34 ( = 5, 13%), and S27 ( = 5, 13%) mutations. Locations and histological subtype of -mutated melanoma varied; none were reported as showing deep penetrating nevus-like morphology. The most frequent concurrent activating mutations were V600 ( = 21, 55%) and Q61 ( = 13, 34%). In our cohort, four of seven (58%) and one of nine (11%) patients treated with targeted therapy (BRAF and MEK Inhibitors) or immune-checkpoint therapy, respectively, showed disease control (partial response or stable disease). In summary, mutations are associated with a unique melanocytic tumor type in benign tumors (nevi), which can be applied in a diagnostic setting. In advanced disease, no clear characteristics distinguishing -mutant from other melanomas were observed; however, studies of larger, optimally prospective, cohorts are warranted.