BRAF functional domains and comparison between the 1-2-3 and A-B-C BRAF classification systems. The 1-2-3 BRAF mutation classification is based on in vitro assays of Ras pathway activity. However, as it has not been validated by the analysis of native mutations in isogenic cells, we explored, in parallel, a simpler classification based on the mutation location in functional domains: A, codon 600; B, other active site mutations flanking codon 600 (581–601); and C, ATP-binding site mutations (464–469). RBD, Ras-binding domain. (Created with BioRender.com.)