While sentinel lymph node (SLN) biopsy is typically offered to patients with primary cutaneous melanomas (PCMs) of ≥1mm depth, not all SLNs are positive using this cut-off. To ascertain whether this was genetically regulated, genetic analysis was performed using an augmented enrichment-based next-generation DNA and RNA sequencing assay in SLN- [Group 1, n=8, mean depth 1.3mm] and SLN+ PCMs [Controls, Group 2, n=4, mean depth 1.4mm]. Group 1: Mean number of mutations was 21 (range 3-48) with most frequent mutations in NF1 (75%) followed by TP53 (63%), CDKN2A and BRAF (38%) and NRAS (25%). Group 2: Mean number of mutations was 9.5 (range 5-18) with mutations in NRAS and BRAF being the most frequent (50%) followed by ATM, CDKN2A, CDKN2B, and NOTCH1 (25%). Increased frequency of NF1 inactivating mutations in Group 1 provides provocative early data that the presence of NF1 mutations might confer a less aggressive phenotype.