B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. BRAF mutations are present in approximately 50% to 60% of cutaneous melanomas and are also present at lower frequencies in other melanoma subtypes. Mutations at protein residue G464 are rare in melanoma and have not been reported in previous sequencing studies. The G464V mutation results in an amino acid substitution within the highly conserved motif of the kinase domain. This specific mutation is a low frequency cancer-associated variant classified as an intermediate activity mutant that moderately increases ERK activation and can transform cells. The predictive significance of this mutation needs further study. Clinical correlation is recommended.