{"entity":{"id":"braf-class-ii-iii","kind":"biomarker","name":"BRAF class II and class III mutations (non-V600)","aka":["BRAF class II","BRAF class III","non-V600 BRAF","BRAF K601E","BRAF G469A","BRAF D594G","atypical BRAF mutation","BRAF non-V600E"],"tldr":"Class II and III BRAF mutations sit outside codon 600 and signal as pairs (class II) or by leaning on RAS (class III). Approved BRAF inhibitors do not work on them, and no drug is yet approved for them; pan-RAF inhibitors are in trials.","summary":"Class II mutations (K601E, G469A, L597 and others, plus fusions and in-frame deletions) form RAS-independent dimers; class III mutations (D594, G466, N581) are kinase-impaired and amplify upstream RAS or receptor signalling. Neither responds to the monomer-selective inhibitors vemurafenib, dabrafenib or encorafenib, and the labels state the drugs are not indicated for BRAF wild-type tumours without addressing these classes. No approval exists: tovorafenib, a type II RAF inhibitor, is approved only for paediatric low-grade glioma with BRAF fusion or V600 mutation, and trials of pan-RAF inhibitors and MEK inhibitors (for example the NCI-MATCH sub-protocol of trametinib for non-V600 BRAF, and the tovorafenib FIREFLY-2 programme) define the group. The classification is from Yao et al. (Cancer Cell 2015, Nature 2017).","asOf":"2026-09-23","links":[{"label":"OJEMDA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ea3a9631-3a66-6a7c-e053-2995a90ae2ad"}],"tags":["biomarker","braf","no-approval"],"related":["braf-v600e","braf-fusion"],"cancers":["melanoma","nsclc","colorectal","thyroid"],"sections":[],"technologies":[],"targets":[],"drugs":["tovorafenib","trametinib"],"companies":[],"institutions":[],"pathways":[],"terms":["braf-v600-mutation","driver-passenger-model"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"braf","measurement":"sequencing-variant","scoringRule":{"text":"A BRAF mutation outside codon 600 classified by mechanism: class II (RAS-independent dimers, kinase-activated) or class III (kinase-impaired, RAS-dependent); detected by sequencing.","quote":"BRAF V600 mutations and BRAF fusions","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices (the Ojemda row names V600 mutations and fusions; no companion claim covers class II or III point mutations)"},"thresholds":[],"definedBy":{"label":"Yao et al., Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS, Nature 2017 (the class I to III scheme)","url":"https://doi.org/10.1038/nature23291"},"tests":["foundationone-cdx","tempus-xt","caris-mi-cancer-seek","trusight-oncology-comprehensive"],"assays":[],"companionDiagnostics":[],"forPatient":"A BRAF mutation that is not V600E or V600K usually means the approved BRAF tablets are not expected to work. There is no approved drug for these classes yet; ask about trials of pan-RAF or MEK inhibitors, and about the other treatments for your cancer type, which are unchanged by this result."},"route":"/biomarkers/braf-class-ii-iii/","neighbours":{"biomarker":[{"id":"braf-fusion","kind":"biomarker","name":"BRAF fusion or rearrangement","route":"/biomarkers/braf-fusion/"},{"id":"braf-v600e","kind":"biomarker","name":"BRAF V600E (and V600K)","route":"/biomarkers/braf-v600e/"}],"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"thyroid","kind":"cancer","name":"Thyroid cancer","route":"/cancers/thyroid/"}],"drug":[{"id":"tovorafenib","kind":"drug","name":"Tovorafenib","route":"/drugs/tovorafenib/"},{"id":"trametinib","kind":"drug","name":"Trametinib","route":"/drugs/trametinib/"}],"term":[{"id":"braf-v600-mutation","kind":"term","name":"BRAF V600E mutation","route":"/terms/braf-v600-mutation/"},{"id":"driver-passenger-model","kind":"term","name":"Driver and passenger mutations: the refined somatic mutation theory","route":"/terms/driver-passenger-model/"}],"target":[{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"}]}}