PURPOSE: Cardiac angiosarcoma is a rare, aggressive malignancy with limited treatment options. Both sporadic and familial cases occur, with recent links to germline POT1 mutations. The genomic landscape of this disease is poorly understood. EXPERIMENTAL DESIGN: We conducted comprehensive genomic profiling of cardiac angiosarcoma to assess the burden of germline predisposition and identify other recurrent genomic alterations of clinical significance. RESULTS: Six patients were female, and four were male. The median age at presentation was 40 years (range, 21-69 years). All cases with available follow-up exhibited an aggressive clinical course (6/8 patients died of disease). KDR alterations, including novel structural variants, were found in 9/11 cases at a rate significantly higher than that in noncardiac angiosarcomas. POT1 mutations were present in 45.5% of cardiac angiosarcoma cases. In three of five POT1-mutant cases, the germline status was confirmed through testing of normal tissue, and in one additional case, the germline status was inferred with high probability through allele frequency analysis. Additionally, we identified novel recurrent MED12 exon 2 mutations in POT1 wild-type cardiac angiosarcoma, suggesting an alternative path to cardiac angiosarcoma oncogenesis. CONCLUSIONS: Cardiac angiosarcoma demonstrates a unique genetic profile, distinct from noncardiac angiosarcoma. This study highlights the role of germline POT1 burden on cardiac angiosarcoma development and demonstrates recurrent MED12 alterations for the first time. The reported KDR variants provide a potential avenue for the treatment of this aggressive disease. Given the prevalence of germline POT1 mutations reported in this study, germline genetic testing should be considered in patients diagnosed with cardiac angiosarcoma.