This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.2947 ; We identify families in which early onset multiple primary melanoma co-segregates with inactivating mutations in the protection of telomeres 1 (POT1) gene. We show that missense mutations of POT1 in three families alter key residues of the oligonucleotide- /oligosaccharide-binding (OB) domains, disrupting telomere binding, leading to increased telomere length. Our results suggest POT1 mutations strongly predispose to melanoma formation. ; D.J.A., C.D.R.-E., Z.D., J.Z.L., J.C.T., M.P. and T.M.K. were supported by Cancer Research UK and the Wellcome Trust (WT098051). C.D.R.-E. was also supported by the Consejo Nacional de Ciencia y Tecnolog?a of Mexico. K.A.P. and A.M.D. were supported by Cancer Research UK (grants C1287/A9540 and C8197/A10123) and by the Isaac Newton Trust. N.K.H. was supported by a fellowship from the National Health and Medical Research Council of Australia (NHMRC). L.G.A. was supported by an Australia and New Zealand Banking Group Limited Trustees PhD scholarship. A.L.P. is supported by Cure Cancer Australia. The work was funded in part by the NHMRC and Cancer Council Queensland. The work of N.A.G. was in part supported by the Dutch Cancer Society (UL 2012-5489). M.H., J.A.N.-B. and D.T.B. were supported by Cancer Research UK (programme awards C588/A4994 and C588/A10589 and the Genomics Initiative). C.L.-O., A.J.R. and V.Q. are funded by the Spanish Ministry of Economy and Competitiveness through the Instituto de Salud Carlos III (ISCIII), the Red Tem?tica de Investigaci?n del C?ncer (RTICC) del ISCIII and the Consolider-Ingenio RNAREG Consortium. C.L.-O. is an investigator with the Bot?n Foundation.