BAP1 tumour predisposition syndrome

BAP1-TPDS is a multi-system adult-onset cancer-predisposition syndrome with broad intra- and interfamilial variability. Affected individuals frequently develop more than one primary cancer. The characteristic cutaneous lesion is the BAP1-inactivated melanocytic tumour (BIMT; formerly termed atypical Spitz tumour). Uveal melanoma is the most frequently reported malignancy, occurring in 36% of probands and 16% of relatives. Malignant mesothelioma affects 25% of probands and shows a markedly higher peritoneal-to-pleural ratio. Cutaneous melanoma occurs in 13% of affected individuals, frequently as multiple primaries and at a younger median age of 39 years. , predominantly of clear-cell morphology, affects 10% of probands and relatives.

The prevalence of BAP1-TPDS is unknown.

BAP1-TPDS is caused by heterozygous germline pathogenic variants in BAP1. BAP1 encodes BRCA1-associated protein 1, a nuclear deubiquitinating enzyme that participates in chromatin-associated multiprotein complexes regulating cellular proliferation and homologous-recombination repair of DNA double-strand breaks. Pathogenicity follows a two-hit loss-of-function model: the germline variant produces BAP1 haploinsufficiency, with tumour development requiring somatic inactivation of the remaining wild-type allele and complete loss of BAP1 tumour-suppressor activity. Most reported pathogenic variants are loss-of-function; missense variants within the ubiquitin carboxyl-terminal hydrolase domain have also been described.

BAP1-TPDS is inherited in an autosomal dominant manner. Each offspring of an affected individual has a 50% probability of having inherited the heterozygous germline pathogenic variant.

BAP1-TPDS is diagnosed primarily by molecular genetic testing. Identification of a heterozygous germline pathogenic variant in BAP1 establishes the diagnosis. Testing is prompted by the presence of one or more characteristic tumours, particularly when occurring at younger-than-typical age or in combination, and by a family history consistent with hereditary cancer predisposition.

Main differential diagnoses include:

• CDKN2A-related familial atypical multiple mole melanoma-pancreatic carcinoma syndrome: overlapping cutaneous melanoma and mesothelioma risk with additional pancreatic cancer susceptibility; CDKN2A
• : cutaneous and uterine leiomyomas alongside renal cell carcinoma; FH
• : clear-cell RCC, retinal and CNS haemangioblastomas, phaeochromocytomas; VH

• Establishing the diagnosis through identification of the underlying pathogenic variant provides clarity for the affected individual and family.
• It enables specific and individualised surveillance and clinical management tailored to the molecular diagnosis, which is a prerequisite for targeted medical care; the choice of surveillance measures lies with the treating physicians in consultation with the affected individual.
• It allows predictive testing of at-risk family members, enabling those who have inherited the pathogenic variant to access surveillance, while those who have not are spared unnecessary follow-up.

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• Lalloo F, Kulkarni A, Chau C, Nielsen M, Sheaff M, Steele J, et al. Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome. Eur J Hum Genet. 2023;31(11):1261-9. doi:10.1038/s41431-023-01448-z. PMID:; PMCID: PMC10620132.
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