BRAF is part of the mitogen-activated protein kinase (MAPK) signaling pathway. BRAF G466V is a missense mutation which impairs BRAF kinase activity but paradoxically activates MEK and ERK through transactivation of c-RAF. This variant is associated with decreased cell proliferation and cell viability as compared to wild-type BRAF. This variant is a rare BRAF mutation and accounts for < 1% of BRAF mutations in colorectal adenocarcinoma. A single preclinical study of BRAF G466V in colon cancer demonstrated sensitivity to anti-EGFR tyrosine kinase therapy (cetuximab) and a MEK inhibitor (trametinib), however, there was no benefit seen with the RAF inhibitor vermurafinib. The clinicopathologic significance of BRAF G466V remains to be fully elucidated.