Clinical characteristics: BAP1 tumor predisposition syndrome (BAP1-TPDS) is associated with an increased risk for a specific skin lesion, BAP1-inactivated melanocytic tumors (BIMT; formerly called atypical Spitz tumors), and the following cancers, in descending order of frequency: uveal (eye) melanoma (UM), malignant mesothelioma (MMe), cutaneous melanoma (CM), renal cell carcinoma (RCC), basal cell carcinoma (BCC), meningioma, and cholangiocarcinoma. Onychopapillomas, hepatocellular carcinoma, and ovarian sex cord-stromal tumors may also be associated with BAP1-TPDS. Affected individuals can have more than one type of primary cancer. In general, the median age of onset of these tumors is younger than in the general population. UM tends to be a more aggressive class 2 tumor with higher risk for metastasis and reduced survival compared to UM occurring in the general population. RCC is usually of clear cell morphology, but other pathologies have been reported. MMe, especially pleural, has better survival and responds better to platinum chemotherapy than MMe not associated with a germline BAP1 pathogenic variant. The penetrance, natural history, life-time cancer risk for carriers, and frequencies of BAP1-associated tumors are yet to be fully determined.

Diagnosis/testing: The diagnosis of BAP1-TPDS is established in a proband by identification of a heterozygous germline pathogenic variant in BAP1 on molecular genetic testing.

Management: Treatment of manifestations: Treatment of CM, BCC, and RCC per established clinical guidelines. UM treatment should be the same as the more aggressive class 2 or monosomy 3 tumors because of the increased aggressiveness of BAP1-related UM. MMe treatment per oncologist familiar with BAP1-related MMe. Meningiomas are usually higher grade / atypical and should be treated accordingly. Treatment of other cancers per established clinical guidelines.

Prevention of primary manifestations: UM: avoid arc-welding. MMe: avoid asbestos exposure (including naturally occurring tremolite and erionite) and smoking. CM and BCC: limit sun exposure, use sunscreen and protective clothing, and perform regular dermatologic examinations.

Surveillance: BIMT, CM, BCC: annual full-body dermatologic examinations beginning at age 18 years; consider follow-up total body photography in those with a large number of skin lesions as needed. UM: annual dilated eye examinations beginning at age 11-18 years or at puberty with referral to ocular oncologist for any pigmented lesions. MMe, RCC: annual clinical evaluation for manifestations of pleurisy, peritonitis, ascites, and/or pleural effusion and RCC beginning at age 30 years; renal/abdominal and chest ultrasound every two years alternating with abdominal and chest MRI every two years beginning at age 30 years.

Agents/circumstances to avoid: Arc welding, asbestos including naturally occurring tremolite and erionite, smoking, unnecessary and prolonged sun exposure, routine chest radiographs, and CT examinations.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of at-risk relatives by molecular genetic testing for the BAP1 pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of surveillance and counseling regarding agents/circumstances to avoid.

Genetic counseling: BAP1-TPDS is inherited in an autosomal dominant manner. Most individuals diagnosed with BAP1-TPDS have an affected parent (an affected parent may have BAP1-related tumors that differ from those of the proband). Some individuals have BAP1-TPDS as the result of a de novo pathogenic variant. Each child of an individual with BAP1-TPDS has a 50% chance of inheriting the BAP1 pathogenic variant. Once a germline BAP1 pathogenic variant has been identified in an affected family member, predictive testing for at-risk family members and prenatal and preimplantation genetic testing are possible.