These authors contributed equally to this work.
A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma
Article first published online: 1 OCT 2012
2012 John Wiley & Sons A/S. Published 2012. This article is a US Government work and is in the public domain in the USA.
Pigment Cell & Melanoma Research
Volume 25, Issue 6, pages 815–818, November 2012
How to Cite
Wadt, K., Choi, J., Chung, J.-Y., Kiilgaard, J., Heegaard, S., Drzewiecki, K. T., Trent, J. M., Hewitt, S. M., Hayward, N. K., Gerdes, A.-M. and Brown, K. M. (2012), A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma. Pigment Cell & Melanoma Research, 25: 815–818. doi: 10.1111/pcmr.12006
- Issue published online: 19 OCT 2012
- Article first published online: 1 OCT 2012
- Accepted manuscript online: 13 AUG 2012 06:45AM EST
- Manuscript Accepted: 6 AUG 2012
- Manuscript Received: 9 MAR 2012
- Division of Cancer Epidemiology and Genetics
- Center for Cancer Research
- Melanoma Research Alliance Team Science Award
- splice mutation;
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.