biomarkersBiomarker

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

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.

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).

Part ofBRAF· BRAFOther readoutsBRAF fusion or rearrangement BRAF V600E All readouts

BRAF: what it is and how drugs act on it · animated schematic, not to scale

Target · the protein and the cell it sits on
Drug · antibody, small molecule, cell or radioligand
Effect · signal, damage or kill

In plain words · BRAF is a signalling kinase mutated in half of melanomas; blocking it with two drugs at once became a template for targeted therapy.

Sequencing No approval threshold

What it means for a patient

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.

Written only from the label or guideline text cited on this page. Not medical advice; your own report and the reading your team gives it come first.

Scoring rule

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.

“BRAF V600 mutations and BRAF fusions”
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 used in approvals

No approval uses this readout as a threshold. It is defined by 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).

Tests that measure it

Tempus xT and xT CDx FoundationOne CDx Caris MI Cancer Seek Illumina TruSight Oncology Comprehensive

Trials that name this readout

Matched on the name and aliases of the readout in the title, setting and summary of each trial; a match is a mention, not proof the readout was an entry criterion.