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

Pigment Cell Melanoma Res. 2012 Nov;25(6):815-8. doi: 10.1111/pcmr.12006. Epub 2012 Oct 1.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Chromosome Segregation / genetics
  • Family
  • Female
  • Humans
  • Male
  • Melanoma / genetics*
  • Molecular Sequence Data
  • Mutation, Missense / genetics*
  • Paraganglioma / genetics*
  • Pedigree
  • RNA Splice Sites / genetics*
  • RNA Splicing / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Skin Neoplasms / genetics*
  • Tumor Suppressor Proteins / genetics*
  • Ubiquitin Thiolesterase / genetics*
  • Uveal Neoplasms / genetics*


  • BAP1 protein, human
  • RNA Splice Sites
  • RNA, Messenger
  • Tumor Suppressor Proteins
  • Ubiquitin Thiolesterase

Supplementary concepts

  • Uveal melanoma