BAP1 is a tumor suppressor gene whose product interacts with BRCA1 and BARD1. Heterozygous germline pathogenic/likely pathogenic (P/LP) variants in the BAP1 gene have been associated with an autosomal dominant hereditary cancer syndrome known as hereditary BAP1 cancer predisposition syndrome, or BAP1 tumor predisposition syndrome (Abdel-Rahman et al., 2011; Pilarski et al., 2016). This condition is associated with an overall increased risk for cancers, but particularly uveal melanomas (UM), malignant mesothelioma (MMe), cutaneous melanomas (CM), clear cell renal carcinoma, and basal cell carcinoma (Pilarski et al., 2016; Masoomian et al., 2018). Melanocytic BAP1-mutated atypical intradermal tumors (MBAITs), a unique form of melanocytic tumor, are present on the skin of the majority of individuals (66.7%) with germline BAP1 P/LP variants (Carbone et al., 2012) and may develop several years before the characteristic malignancies associated with BAP1 (Masoomian et al., 2018). Uveal melanomas associated with germline BAP1 P/LP variants appear to be a more aggressive form of UM, given the high rate of metastatic disease found within this population (Pilarski et al. 2014). It has been suggested that other cancers may be associated with germline BAP1 P/LP variants, including meningiomas, non-small cell lung adenocarcinomas, cholangiocarcinomas, thyroid and breast cancers. It is still unclear whether these additional tumor types are part of the phenotype of this condition, although loss of BAP1 heterozygosity and a higher incidence of these tumors among carriers supports their inclusion in the phenotypic spectrum (Pilarski et al, 2016; Walpole et al., 2018). Penetrance appears to be high with upwards of 80% of individuals with a BAP1 P/LP variant eventually developing one or more cancers (Massomian et al., 2018). 

BAP1 tumor predisposition syndrome should be suspected in an individual who has two or more confirmed BAP1-associated tumors (as listed above) OR an individual who has a confirmed BAP1-associated tumor and has a first or second-degree relative with a confirmed BAP1-associated tumor (Pilarski et al., 2016; Masoomian et al., 2018). Bilateral UM is also an indication for BAP1 testing (Shields et al., 2018).

The frequency of germline BAP1 P/LP variants is not well established, but a recent review suggests a frequency of approximately 2-3% in unselected cases of UM and approximately 22% of familial UM cases (Masoomian et al., 2018). In a study by Abdel-Rahman et al. (2011), one of 53 unrelated patients with UM was found to have a germline BAP1 truncating P/LP variant. In addition, Carbone et al. (2012) performed a meta-analysis of the published studies of germline BAP1 P/LP variants to date, and created two cohorts from nine families: one comprised of 63 germline BAP1-mutated patients and the other of 55 non-mutated patients. This study concluded that the overall occurrence of cancer was significantly greater in the BAP1-mutated cohort compared to the those without a BAP1 P/LP variant, with an odds ratio for cancer risk of 17.39 (95% CI: 6.07-49.83) for the BAP1-mutated cohort (Carbone et al., 2012). More recently, Pilarski et al. (2014) found 3 P/LP variants in BAP1 and 4 variants of uncertain significance in a group of 50 patients suspected to have a hereditary cancer syndrome. Of note, a study conducted by Rai et al. (2016), identified a BAP1 P/LP variant in 19% (6/32) of families who met a diagnosis of familial UM. Panou et al (2018) reported on a series of 198 patients with malignant mesothelioma for whom multi-gene germline testing was performed. Germline P/LP variants were identified in 12% of patients in a total of 13 genes associated with cancer predisposition, with BAP1 accounting for 24% of variants identified.

Many of the cancer risks associated with germline BAP1 P/LP variants for associated tumors are not well-established; however, new data suggests the risk for UM to be close to 3% (Singh et al., 2021). As such, there are no professional society guidelines for the medical management of individuals who carry BAP1 P/LP variants. Although the specific phenotype of this hereditary cancer predisposition syndrome is still being characterized, multiple groups have suggested surveillance strategies to include routine ophthalmologic examinations for UM, regular full body dermatologic examination, and abdominal ultrasound or MRI to screen for signs of renal cell carcinoma and/or mesothelioma (Pilarski et al., 2016; Star et al., 2018; Lalloo et al., 2023). Avoidance of asbestos, smoking, and prolonged sun exposure is also suggested (Pilarski et al., 2016; Star et al., 2018; Lalloo et al., 2023).