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Intronic alterations in BRCA1 and BRCA2: effect on mRNA splicing fidelity and expression

✍ Scribed by Xiaowei Chen; Tuyet-Trinh N. Truong; JoEllen Weaver; Betsy A. Bove; Kimberly Cattie; Brock A. Armstrong; Mary B. Daly; Andrew K. Godwin

Publisher: John Wiley and Sons
Year: 2006
Tongue: English
Weight: 882 KB
Volume: 27
Category: Article
ISSN: 1059-7794
DOI: 10.1002/humu.20319

No coin nor oath required. For personal study only.

✦ Synopsis

Communicated by Haig H. Kazazian

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.44111G4A/IVS711G4A, and c.49861 6T4G/IVS1616T4G) and two BRCA2 variants (c.848711G4A/IVS1911G4A and c.8632-2A4 G/IVS20-2A4G). 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.44111G4A, c.498616T4G, and c.8632-2A4G) with premature termination codons were highly unstable and were unlikely to encode for abundant expression of a mutant protein. Three variants of BRCA1 (c.21213A4G/ IVS513A4G, c.59318A4G/IVS918A4G, and c.4986-20A4G/IVS16-20A4G) and four variants of BRCA2 (c.516-19C4T/IVS6-19C4T, c.7976-4_7976_3delTT/IVS17-4delTT, c.8487119A4G/IVS191 19A4G, and c.9256-18C4A/IVS24-18C4A) 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.

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