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Type: Journal article
Title: Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide
Author: Walpole, S.
Pritchard, A.L.
Cebulla, C.M.
Pilarski, R.
Stautberg, M.
Davidorf, F.H.
de la Fouchardière, A.
Cabaret, O.
Golmard, L.
Stoppa-Lyonnet, D.
Garfield, E.
Njauw, C.N.
Cheung, M.
Turunen, J.A.
Repo, P.
Järvinen, R.S.
van Doorn, R.
Jager, M.J.
Luyten, G.P.M.
Marinkovic, M.
et al.
Citation: Journal of the National Cancer Institute, 2018; 110(12):1328-1341
Publisher: Oxford University Press
Issue Date: 2018
ISSN: 0027-8874
Statement of
Sebastian Walpole Antonia L Pritchard Colleen M Cebulla Robert Pilarski Meredith Stautberg ... Nicola Poplawski ... et al.
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tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS.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.
Keywords: Phenotype; mesothelioma; neoplasms; pathogenicity; bap1 gene
Rights: © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (
DOI: 10.1093/jnci/djy171
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