Germline mutations in the BAP1 gene predispose to malignant mesothelioma. This study identified BAP1 mutations in two families with a high incidence of mesothelioma. Somatic BAP1 alterations were found in familial mesotheliomas, indicating biallelic inactivation. Additionally, some BAP1 mutation carriers developed uveal melanoma. Germline BAP1 mutations were also found in two of 26 sporadic mesotheliomas, both of which had a history of uveal melanoma. Truncating mutations and aberrant BAP1 expression were common in sporadic mesotheliomas without germline mutations. These results reveal a BAP1-related cancer syndrome characterized by mesothelioma and uveal melanoma. The study suggests that other cancers may also be involved, and that mesothelioma predominates upon asbestos exposure. Malignant mesotheliomas are aggressive tumors resistant to current therapies and are primarily associated with asbestos exposure. The study found that BAP1 mutations are linked to familial mesothelioma, and that these mutations may also predispose to uveal melanoma. The study also found that BAP1 mutations are associated with a novel hereditary cancer syndrome that predisposes to mesothelioma, uveal melanoma, and potentially other cancers. The study highlights the importance of identifying individuals at high risk of mesothelioma for early intervention. The study found that BAP1 mutations are associated with a BAP1-related cancer syndrome characterized by mesothelioma and uveal melanoma. The study also found that BAP1 mutations may be sufficient to cause mesothelioma. The study provides the first demonstration that genetics influences the risk of mesothelioma, a cancer linked to mineral fiber carcinogenesis. The study suggests that more genes will be found associated with elevated risk of mesothelioma in addition to BAP1. The study also found that BAP1 mutations are associated with a novel hereditary cancer syndrome that predisposes to mesothelioma, uveal melanoma, and potentially other cancers. The study highlights the importance of identifying individuals at high risk of mesothelioma for early intervention.Germline mutations in the BAP1 gene predispose to malignant mesothelioma. This study identified BAP1 mutations in two families with a high incidence of mesothelioma. Somatic BAP1 alterations were found in familial mesotheliomas, indicating biallelic inactivation. Additionally, some BAP1 mutation carriers developed uveal melanoma. Germline BAP1 mutations were also found in two of 26 sporadic mesotheliomas, both of which had a history of uveal melanoma. Truncating mutations and aberrant BAP1 expression were common in sporadic mesotheliomas without germline mutations. These results reveal a BAP1-related cancer syndrome characterized by mesothelioma and uveal melanoma. The study suggests that other cancers may also be involved, and that mesothelioma predominates upon asbestos exposure. Malignant mesotheliomas are aggressive tumors resistant to current therapies and are primarily associated with asbestos exposure. The study found that BAP1 mutations are linked to familial mesothelioma, and that these mutations may also predispose to uveal melanoma. The study also found that BAP1 mutations are associated with a novel hereditary cancer syndrome that predisposes to mesothelioma, uveal melanoma, and potentially other cancers. The study highlights the importance of identifying individuals at high risk of mesothelioma for early intervention. The study found that BAP1 mutations are associated with a BAP1-related cancer syndrome characterized by mesothelioma and uveal melanoma. The study also found that BAP1 mutations may be sufficient to cause mesothelioma. The study provides the first demonstration that genetics influences the risk of mesothelioma, a cancer linked to mineral fiber carcinogenesis. The study suggests that more genes will be found associated with elevated risk of mesothelioma in addition to BAP1. The study also found that BAP1 mutations are associated with a novel hereditary cancer syndrome that predisposes to mesothelioma, uveal melanoma, and potentially other cancers. The study highlights the importance of identifying individuals at high risk of mesothelioma for early intervention.