Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide

Abstract

Background: The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors.

Methods: We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided.

Results: The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P < .001), mesothelioma (P < .001), cutaneous melanoma (P < .001), and nonmelanoma skin cancer (P < .001).

Conclusions: This analysis substantially increases the number of pathogenic BAP1 germline variants and refines the phenotype. It highlights the need for a curated registry of germline variant carriers for proper assessment of the clinical phenotype of the BAP1-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research.

Figure 1.

Reported missense variants plotted proportional to their frequency along the BAP1 gene with the functional domains shown. Variants that have evidence supporting pathogenicity are marked as red. The four blocks underneath each variant indicate their presence in the indicated databases. Database versions used for these metadata were: ClinVar 20170705, COSMIC v81 20170508, dbSNP 20170710, and gnomAD r2.0.1. BARD1 = BARD1 binding domain; BRCA1 = BRCA1 binding domain; cosmic = Catalogue of Somatic Mutations in Cancer; CCD = coiled-coil domain; dbSNP = Database of Single-Nucleotide Polymorphisms; gnomAD = Genome Aggregation Database; HBM = HCF binding motif (minimal tetrapeptide HCF1 binding motif); HCFC1 = HCFC1 binding domain; NLS = nuclear localization signal; UCH = ubiquitin carboxy-terminal hydrolase; ULD = Uch37-like domain; YY1 = YY1 binding domain.

Figure 2.

The age of onset of all tumors presenting in variant carriers included in this study shown as box and whisker plots. Tumors are grouped together in the “all” group and then broken down into subgroups of the main BAP1-associated tumors. CM = cutaneous melanoma; Meso = mesothelioma; Renal = nonmelanoma of skin, liver, and meningioma; UM = uveal melanoma. All tumors are separated into the type of variant of the individual. M = missense; N = null. Tumors of carriers with missense variants that have evidence supporting pathogenicity (ie, those asterisked in Supplementary Table 2, available online) are marked red. P values were calculated using a two-sided Mann-Whitney test.