The identification of the genetic basis in familial breast cancer is important for treatment and prevention. The aim of this project proposal is to develop new, comprehenisve molecular diagnostic tests and specialized functional assays to unravel the genetic basis of the disease in the largest possible proportion of patients and families. To reach these goals the expertise and patient collections from 3 university hospitals will be bundled. For the classification of BRCA 1/2 variants of unknown clinical significance (UVs) functional assays will be developed and evaluated for subsequent implementation in a diagnostic laboratory. A next generation sequencing approach targeting all known breast cancer genes and predisposing genetic factors will be used in a large cohort of patients to assess their role, and to further fine tune the associated risk estimates. for selected, high risk families an exome sequencing approach will be applied allowing the identification of novel breast cancer genes.