The prevalence of constitutively activating mutations in the BRAF oncogene in cutaneous melanoma has been reported as ranging between 40 and 60%. However this is in a biased population eligible for clinical trials or treated at academic referral centers. The true prevalence in the general population with metastatic melanoma is unknown and may be lower than initially reported. We aim to assess the overall prevalence of BRAF, NRAS and KIT mutations in a cohort of 700 patients with Stage IIIC unresected and IV melanoma tested between July 2009 and July 2013 at Melanoma Institute Australia and affiliated institutions. We will also compare the prevalence at different time points as testing methodology evolved and targeted therapies became available outside of the setting of clinical trials. Preliminary analysis of our data showed the overall BRAF mutation prevalence was 42%. In the subgroup tested more recently using the OncoCarta platform (since April 2012) the rate was as low as 37%, and the proportion of non-V600 mutations was higher then expected, including MAP Kinase inhibitor responsive mutations K601 and L597. Clinicopathological factors and testing techniques will be examined to determine the cause for the difference. Prevalence of NRAS and KIT mutations are consistent with published data, at 18% and 3% respectively. Data collection and statistical analysis is ongoing and the full results up until 1 July 2013 will be presented. Establishing the true prevalence of BRAF and other drug-responsive mutations is critical to guide appropriate testing strategies, design of clinical trials and funding of targeted therapies.