A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma

Karin Wadt, Jiyeon Choi, Joon Yong Chung, Jens Kiilgaard, Steffen Heegaard, Krzysztof T. Drzewiecki, Jeffrey M. Trent, Stephen M. Hewitt, Nicholas K. Hayward, Anne Marie Gerdes, Kevin M. Brown

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


Inactivating germ line BRCA1-associated protein-1 (BAP1) mutations have recently been reported in families with uveal or cutaneous malignant melanoma (UMM, CMM), mesothelioma, and meningioma. Although apparently predisposing to a wide range of tumors, the exact tumor spectrum associated with germ line BAP1 mutations has yet to be established. Here, we report a novel germ line BAP1 splice mutation, c.1708C>G (p.Leu570fs*40), in a multiple-case Danish UMM family with a spectrum of other tumors. Whole-exome sequencing identified an apparent missense mutation of BAP1 in UMM, CMM, as well as paraganglioma, breast cancer, and suspected mesothelioma cases in the family. Bioinformatic analysis and splicing assays demonstrated that this mutation creates a strong cryptic splice donor, resulting in aberrant splicing and a truncating frameshift of the BAP1 transcript. Somatic loss of the wild-type allele was also confirmed in the UMM and paraganglioma tumors. Our findings further support BAP1 as a melanoma susceptibility gene and extend the potential predisposition spectrum to paraganglioma. 2012 John Wiley & Sons A/S. Published 2012. This article is a US Government work and is in the public domain in the USA.

Original languageEnglish (US)
Pages (from-to)815-818
Number of pages4
JournalPigment Cell and Melanoma Research
Issue number6
StatePublished - Nov 2012
Externally publishedYes


  • BAP1
  • Melanoma
  • Paraganglioma
  • Splice mutation

ASJC Scopus subject areas

  • Oncology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Dermatology


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