EGAGenomicsN/Ahttps://ega-archive.org/datasets/EGAD0000100001689EGA dataset EGAD00001000016EGADeleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.POT1 loss-of-function variants predispose to familial melanoma.Robles-Espinoza Carla Daniela CD, Harland Mark M, Ramsay Andrew J AJ, Aoude Lauren G LG, Quesada Víctor V, Ding Zhihao Z, Pooley Karen A KA, Pritchard Antonia L AL, Tiffen Jessamy C JC, Petljak Mia M, Palmer Jane M JM, Symmons Judith J, Johansson Peter P, Stark Mitchell S MS, Gartside Michael G MG, Snowden Helen H, Montgomery Grant W GW, Martin Nicholas G NG, Liu Jimmy Z JZ, Choi Jiyeon J, Makowski Matthew M, Brown Kevin M KM, Dunning Alison M AM, Keane Thomas M TM, López-Otín Carlos C, Gruis Nelleke A NA, Hayward Nicholas K NK, Bishop D Timothy DT, Newton-Bishop Julia A JA, Adams David J DJfalseEGAS00001000017-sc-20110505 - samplesFamilial Melanoma Sequencing2021-05-27 15:56:37EGAD00001000016960624686849EGAC00001000205EGAS00001000017