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00925njm 22002777a 4500 dc Calvete, Oriol author Martinez, Paula author Garcia-Pavia, Pablo author Benitez-Buelga, Carlos author Paumard-Hernandez B author Fernandez, Victoria author Dominguez, Fernando author Salas, Clara author Romero-Laorden, Nuria author Garcia-Donas, Jesus author Carrillo, Jaime author Perona, Rosario author Carlos Trivino, Juan author Andrés, Raquel author Maria Cano, Juana author Rivera, Barbara author Alonso-Pulpon, Luis author Setien, Fernando author Esteller, Manel author Rodriguez Perales, Sandra author Bougeard, Gaelle author Frebourg, Tierry author Urioste, Miguel author Blasco, MA author Benitez, Javier author 2015 Cardiac angiosarcoma (CAS) is a rare malignant tumour whose genetic basis is unknown. Here we show, by whole-exome sequencing of a TP53-negative Li-Fraumeni-like (LFL) family including CAS cases, that a missense variant (p.R117C) in POT1 (protection of telomeres 1) gene is responsible for CAS. The same gene alteration is found in two other LFL families with CAS, supporting the causal effect of the identified mutation. We extend the analysis to TP53-negative LFL families with no CAS and find the same mutation in a breast AS family. The mutation is recently found once in 121,324 studied alleles in ExAC server but it is not described in any other database or found in 1,520 Spanish controls. In silico structural analysis suggests how the mutation disrupts POT1 structure. Functional and in vitro studies demonstrate that carriers of the mutation show reduced telomere-bound POT1 levels, abnormally long telomeres and increased telomere fragility. Nat Commun. 2015; 6:8383 10.1038/ncomms9383 2041-1723 Nature Communications 26403419 http://hdl.handle.net/20.500.12105/5394 TELOMERE LENGTH QUANTITATIVE PCR PROTEIN VARIANTS REQUIREMENTS MAINTENANCE PREDISPOSE EXPRESSION PREDICTION PROTECTION A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families