Communicated by Haig H. Kazazian
Article first published online: 17 APR 2006
This article is a U.S. Government work and is in the public domain in the U.S.A. Published in 2006 by Wiley-Liss, Inc.
Volume 27, Issue 5, pages 427–435, May 2006
How to Cite
Chen, X., Truong, T.-T. N., Weaver, J., Bove, B. A., Cattie, K., Armstrong, B. A., Daly, M. B. and Godwin, A. K. (2006), Intronic alterations in BRCA1 and BRCA2: effect on mRNA splicing fidelity and expression. Hum. Mutat., 27: 427–435. doi: 10.1002/humu.20319
This article is a US government work and, as such, is in the public domain in the United States of America.
- Issue published online: 17 APR 2006
- Article first published online: 17 APR 2006
- Manuscript Accepted: 14 DEC 2005
- Manuscript Received: 2 SEP 2005
- Cheryl Herman and the Eileen Stein-Jacoby Fund, Commonwealth of Pennsylvania
- National Cancer Institute. Grant Number: Ovarian Cancer SPORE P50 CA83638
- National Institutes of Health. Grant Number: U01 CA69631
- Department of Defense. Grant Numbers: W81XWH-04-1-0573, DAMD17-03-1-0707, DAMD17-03-1-0312
- nonsense-mediated mRNA decay;
- variants of unknown significance;
- breast cancer;
- ovarian cancer
Germline mutations in the human breast cancer susceptibility genes BRCA1 and BRCA2 account for the majority of hereditary breast and ovarian cancer. In spite of the large number of sequence variants identified in BRCA1 and BRCA2 mutation analyses, many of these genetic alterations are still classified as variants of unknown significance (VUS). In this study, we evaluated 12 BRCA1/2 intronic variants in order to differentiate their pathogenic or polymorphic effects on the mRNA splicing process. We detected the existence of aberrant splicing in three BRCA1 variants (c.301-2delA/IVS6-2delA, c.441+1G>A/IVS7+1G>A, and c.4986+6T>G/IVS16+6T>G) and two BRCA2 variants (c.8487+1G>A/IVS19+1G>A and c.8632-2A>G/IVS20-2A>G). All but one of the aberrant transcripts arise from mutations affecting the conserved splice acceptor or donor sequences and all would be predicted to result in expression of truncated BRCA1 or BRCA2 proteins. However, we demonstrated that four of these splice-site mutations (i.e., c.301-2delA, c.441+1G>A, c.4986+6T>G, and c.8632-2A>G) with premature termination codons were highly unstable and were unlikely to encode for abundant expression of a mutant protein. Three variants of BRCA1 (c.212+3A>G/IVS5+3A>G, c.593+8A>G/IVS9+8A>G, and c.4986-20A>G/IVS16-20A>G) and four variants of BRCA2 (c.516-19C>T/IVS6-19C>T, c.7976-4_7976_3delTT/IVS17-4delTT, c.8487+19A>G/IVS19+19A>G, and c.9256- 18C>A/IVS24- 18C>A) in our studies show no effects on the normal splicing process, and they are considered to be benign polymorphic alterations. Our studies help to clarify the aberrant splicing in BRCA1 and BRCA2 as well as provide information that can be used clinically to help counsel breast/ovarian cancer prone families. Hum Mutat 27(5), 427–435, 2006. Published 2006 Wiley-Liss, Inc.