Classes II and III are centered on the active site, especially, around the chelating region of the phosphate tail with Mg 2+. 52 of them are situated in the kinase domain. At this day and based on the SPHN/SPO, ClinVar 6, LOVD 7 and JAX-clinical Knowledgebase 8 databases, 373 BRAF mutations were reported, including 76 pathogenic ones (gain or loss of function). Classes II and III are more diverse as they comprise more positions and mutation types (missense, insertion, deletion and insertion-deletion, and gene fusions) and few positions can even lead to a class II or III depending on the variant (BRAF p.G469A is a class IIВ mutation, while BRAF p.G469E isВ a class III one e.g.). Class I involves only missense mutations of Val600. Most of them are located in the kinase domain (Fig. Three classes of BRAF mutations have been described based on their effects. Mutations in the kinase domain can impact the protein structure and functionality, leading to pathogenic effects like a gain or decrease of function, which is crucial to know to propose an appropriate treatment to the individual patient in the context of personalized oncology. Most mutations of these three classes affect the kinase domain of the protein, which is the site of the catalytic activity where the hydrolyzation of the adenosine triphosphate (ATP) into adenosine diphosphate (ADP) occurs to phosphorylate and activate MEK1 or MEK2, and thus, affect the pathway itself. Class III mutations are RAS-dependent homo or heterodimers and lead to a decrease or loss of function. The activation induced by these mutations is lower than in class I. Class II mutations lead to a high and moderate RAS-independent BRAF dimeric activation. These variants are all missense mutations of Val600, which resides in the activation loop of the protein. Class I mutations lead to a high activation of RAS-independent monomeric BRAF. Mutations effects analysis has identified three mutation classes 3 (Fig. Depending on the position and the amino acid variation, a mutation can have different effects on the functionality of BRAF that could impact treatment possibilities for the patient. Indeed, several BRAF mutations have been detected in human cancers and characterized as pathogenic, making it an important onco-driver gene 2. Then, active RAS-GTP will activate BRAF which will be able to form dimers and trigger the kinase cascade involving MEK1/2 and ERK1/2, leading to the activation of cell growth and division.Д«RAF is therefore a central serine/threonine-protein kinase of the MAP kinase pathway and mutations of this protein can lead to important pathogenic effects. Inactive RAS-guanosine-5вЂ™-diphosphate (GDP) complex can be activated by SOS from the newly formed complex EGFR/GRB2/SOS, which induces the exchange of GDP to guanosine-5К№-triphosphate (GTP). The process is initiated by the binding of an extracellular signaling molecule to the transmembrane kinase receptor EGFR, leading to its dimerization and auto-phosphorylation, and thus, allowing GRB2 interaction, triggering the possibility to form the complex EGFR/GRB2/SOS. The mitogen-activated protein (MAP) kinase signaling pathway, also called RAS/RAF/MEK/ERK pathway, regulates the cell growth and division via a cascade of kinase phosphorylations 1. This new and fast predictive tool will help oncologists to tackle potential pathogenic BRAF mutations and to propose the most appropriate treatment for their patients. Using a logistic regression model and features including structural information, we were able to predict the classes of known mutations with an accuracy of 90%. As class I only involves missense mutations of Val600, we focused on the mutations of classes II and III, which are more diverse and challenging to predict. To overcome this issue, we developed a new in silico tool based on machine learning approaches to predict the potential class of a BRAF missense variant. However, this information is lacking new and experimentally uncharacterized BRAF mutations detected in a patient biopsy. Discerning the class of a BRAF mutation permits to adapt the treatment proposed to the patient. Several pathologic BRAF variants were grouped in three different classes (I, II and III) based on their effects on the protein activity and pathway. The BRAF kinase is attracting a lot of attention in oncology as alterations of its amino acid sequence can constitutively activate the MAP kinase signaling pathway, potentially contributing to the malignant transformation of the cell but at the same timeВ rendering it sensitive to targeted therapy.

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