BRAF V600E is, globally, the most frequent mutation observed in cutaneous melanoma patients, accounting for 70–88% of all known V600 BRAF mutations [16]. It consists of an amino acid change from valine (V) to glutamic acid (E), resulting in a 480-fold increase in kinase activity (catalytically active conformation) compared with native protein [13]. BRAF V600K is the second most common mutation (10–20% of all V600 BRAF mutations) in cutaneous melanoma and, as V600E mutation, it consists of an amino acid change, with a valine (V) replaced by a lysine (K) [18]. Other rarer codon V600 BRAF mutations, approximately 10% of all V600 mutations, are V600R (<5%), V600D (<5%), V600E2 (<1%), V600M (<1%) and V600G (<1%) [17,19,20]. Cutaneous melanomas harbouring BRAF V600E and V600K mutations, even if similar from a molecular point of view, have distinct clinicopathological features (Table 1). In fact, BRAF V600K-mutant cutaneous melanomas are considered more aggressive than V600E ones, since they have shown less tumour regression and shorter progression-free survival during treatment with combined BRAF and MEK inhibitors, together with a shorter disease-free interval from diagnosis of primary melanoma to the occurrence of first distant metastasis [21,22]. Analysis of BRAF V600K-mutant cutaneous melanoma samples from the Cancer Genome Atlas highlighted, with respect to V600E, an upregulation of energy metabolism, emphasizing their clinical aggressiveness [23]. On the other hand, an older age at diagnosis, a higher degree of cumulative sun-induced damage and a higher mutational burden have been described in V600K-mutant cutaneous melanoma with respect to V600E melanomas, explaining good response to immunotherapy [21,22].

Concerning prognosis, BRAF V600 mutations are statistically significantly associated with reduced OS in cutaneous melanoma patients [24]. In fact, it must be stressed that there is a higher trend of BRAF V600-mutant melanoma, with respect to BRAF wild-type ones, to involve the brain and liver as a first site of metastasis, thus affecting negatively the prognosis of these patients [25]. BRAF V600 mutations also have an important predictive role, since metastatic cutaneous melanoma patients harbouring them do respond to specific inhibitors, as further described. Rare V600 BRAF mutations, such as V600R, V600D and V600M, have been associated with good response to BRAF inhibitors and acceptable OS compared to V600E/K-mutant melanoma patients [26].

BRAF non-V600 mutations, as stated before, are less frequent than V600 ones, and their prognostic and predictive role is, to date, still difficult to elucidate.

L597, K601 and G469 mutations, also known as class II BRAF mutations, determine an increased kinase catalytic activity, different from monomeric V600-mutant protein, through constitutive dimerization. Interestingly, they are located in different regions of the gene: L597 and K601 in the activation segment, whilst G469 in the glycine rich region of BRAF [14]. Even if these mutations do not confer sensitivity to BRAF inhibitors, they activate downstream target proteins, thus explaining sensitivity to MEK inhibitors [27].

Codon D594 and G596 mutations, also known as class III BRAF mutations, have been described as kinase-impairing alterations [28,29]. In fact, different from V600E mutations, which cause hyperactivation of downstream kinase pathways, kinase-impairing mutations cause a reduction in BRAF catalytic activity; these proteins are RAS dependent and have low or absent kinase activity [14,30]. Codon D594 and G596 mutations are rare, < 4% of all melanoma patients, but have been associated with a good prognosis and a more prolonged OS than V600-mutant patients [30]. Codon N581 mutations, very rare, are also kinase-impairing mutations [29].