POT1 and hereditary cancer: Here we identify a new missense variant in POT1 (p.R117C) as responsible of LFL locus specifically associated with CAS and demonstrate that mutation carriers show reduced telomere-bound POT1 levels, abnormally long telomeres and increased telomere fragility, highlighting a new role of POT1 as a high susceptibility gene in familial cancer and opening therapeutical opportunities for prognosis and treatment in families with CAS.