The US Food and Drug Administration (FDA) approved vemurafenib to treat patients 
with metastatic melanoma harboring the BRAF c.1799T>A (p.V600E) mutation. 
However, a subset of melanomas harbor non-p.V600E BRAF mutations, and these data 
are of potential importance regarding the efficacy of current targeted 
therapies. To better understand the BRAF mutation profile in melanomas, we 
retrospectively analyzed data from 1112 primary and metastatic melanomas at our 
institution. The cohort included nonacral cutaneous (n = 774), acral (n = 111), 
mucosal (n = 26), uveal (n = 23), leptomeningeal (n = 1), and metastatic 
melanomas of unknown primary site (n = 177). BRAF mutation hotspot regions in 
exons 11 and 15 were analyzed by pyrosequencing or with the primer extension 
MassARRAY system. A total of 499 (44.9%) specimens exhibited BRAF mutations, 
involving exon 15 [497 (99.6%)] or exon 11 [2 (0.4%)]. p.V600E was detected in 
376 (75.4%) cases; the remaining 123 (24.6%) cases exhibited non-p.V600E 
mutations, of which p.V600K was most frequent [86 (17.2%)]. BRAF mutations were 
more frequent in nonacral cutaneous (51.4%) than acral melanomas [18 (16.2%)] (P 
< 0.001); however, there was no significant difference among cutaneous 
histological subtypes. All mucosal, uveal, and leptomeningeal melanomas were 
BRAF wild type (WT). The high frequency of non-p.V600E BRAF mutations in 
melanoma has important implications because the FDA-approved companion 
diagnostic test for p.V600E detects some but not all non-p.V600E mutations. 
However, the therapeutic efficacy of vemurafenib is not well established in 
these lesions.