Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide

Sebastian Walpole, Antonia L. Pritchard, Colleen M. Cebulla, Robert Pilarski, Meredith Stautberg, Frederick H. Davidorf, Arnaud De La Fouchardière, Odile Cabaret, Lisa Golmard, Dominique Stoppa-Lyonnet, Erin Garfield, Ching Ni Njauw, Mitchell Cheung, Joni A. Turunen, Pauliina Repo, Reetta Stiina Järvinen, Remco Van Doorn, Martine J. Jager, Gregorius P.M. Luyten, Marina MarinkovicCindy Chau, Miriam Potrony, Veronica Höiom, Hildur Helgadottir, Lorenza Pastorino, William Bruno, Virginia Andreotti, Bruna Dalmasso, Giulia Ciccarese, Paola Queirolo, Luca Mastracci, Karin Wadt, Jens Folke Kiilgaard, Michael R. Speicher, Natasha Van Poppelen, Emine Kilic, Rana T. Al-Jamal, Irma Dianzani, Marta Betti, Carsten Bergmann, Sandro Santagata, Sonika Dahiya, Saleem Taibjee, Jo Burke, Nicola Poplawski, Sally J. O'Shea, Julia Newton-Bishop, Julian Adlard, David J. Adams, Anne Marie Lane, Ivana Kim, Sonja Klebe, Hilary Racher, J. William Harbour, Michael L. Nickerson, Rajmohan Murali, Jane M. Palmer, Madeline Howlie, Judith Symmons, Hayley Hamilton, Sunil Warrier, William Glasson, Peter Johansson, Carla Daniela Robles-Espinoza, Raul Ossio, Anneliese de Klein, Susana Puig, Paola Ghiorza, Maartje Nielsen, Tero T. Kivela, Hensin Tsao, Joseph R. Testa, Pedram Gerami, Marc-Henri Stern, Brigitte Bressac-de Paillerets, Mohamed H. Abdel Rahman, Nicholas K. Hayward

Research output: Contribution to journalReview articlepeer-review

159 Citations (Scopus)


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tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS.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.

Original languageEnglish
Pages (from-to)1328-1341
Number of pages14
JournalJournal of the National Cancer Institute
Issue number12
Publication statusPublished - 1 Dec 2018


  • bap1 gene
  • pathogenicity
  • neoplasms
  • mesothelioma
  • phenotype


Dive into the research topics of 'Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide'. Together they form a unique fingerprint.

Cite this