In Switzerland and the Western world cancer disorders remain the major causes of mortality next to cardio-vascular disease. At least 10% of most cancers are recognized to show strong familial clustering indicating univocally hereditary cancer predisposition. However, recent targeted sequencing of known cancer genes in a broader range of cancer patients indicates that only a minority of mutated patients would fulfill the traditional inclusion criteria for hereditary cancer testing. Accordingly, genome studies in unselected control populations indicate that at least 1-3% of the general population in fact carry a mutation in one of the known hereditary cancer syndrome genes. In breast cancer current clinical approaches are geared towards the investigation of such high-risk families for germline mutations in BRCA1 and BRCA2 genes, only. If mutations in these genes are identified in patient’s blood probes, an increased risk for a specific spectrum of subsequent malignancies can be established in the affected patient and respective preventive measures can be initiated. Moreover, ongoing prospective clinical trials are evaluating tailored (preventive) therapy in breast cancer patients with BRCA-mutations. The identification of a heritable predisposing mutation is also of importance for healthy family members. Genetic testing will allow confirming or excluding a familial cancer risk, and preventive measure can be either initiated or reduced. Recent studies indicate that expanding of genetic testing to a broader panel of genes will significantly increase the percentage of patients and families that can be diagnosed with inherited breast cancer conditions, but will lead to a large number of variants of unknown significance, since little is known about genotype-phenotype relationship for these genes. In addition, many more genes expected to contribute to inherited breast cancer are yet to be identified. The aim of this project is therefore to comprehensively identify germline mutations of patients with breast cancer by whole genome sequencing. A selection of thereby identified candidate variants of currently unknown significance will be functionally investigated to increase knowledge about their potential clinical significance and about contributing pathomechanisms in inheritable breast cancer. Through family studies and in-depth genotype-proteotype-phenotype analysis the project aims to generate knowledge about the prevalence and clinical significance of germline mutations in genes and their functional protein products associated with significantly increased cancer risk in Switzerland.