期刊
HUMAN MUTATION
卷 30, 期 1, 页码 107-114出版社
WILEY-LISS
DOI: 10.1002/humu.20811
关键词
BRCA1; BRCA2; unclassified variants; intronic variants; splice-site prediction; RNA analysis; clinical significance
资金
- Dutch Cancer Society [2001-2471]
A large number of sequence variants identified in BRCA1 and BRCA2 cannot be distinguished as either disease causing mutations or neutral variants. These so-called unclassified variants (UVs) include variants that are located in the intronic sequences of BRCA1 and BRCA2. The purpose of this study was to assess the use of splice-site prediction programs (SSPPs) to select intronic variants in BRCA1 and BRCA2 that are likely to affect RNA splicing. We performed in vitro molecular characterization of RNA of six intronic variants in BRCA1 and BRCA2. In four cases (BRCA1, c.81-6T > A and c.49861-5G > T, BRCA2, c.7617+2T > G and c.8754+ 5G > A) a deleterious effect on RNA splicing was seen, whereas the c.135-15_-12del variant in BRCA1 showed no effect on RNA splicing. In the case of the BRCA2 c,68-7T > A variant, RNA analysis was not sufficient to establish the clinical significance. Six SSPPs were used to predict whether an effect oil RNA splicing was expected for these six variants as well as for 23 intronic variants in BRCA1 for which the effect on RNA splicing has been published. Out of a total of 174 predictions, 161 (93%) were informative (i.e., the wild-type splice,site was recognized). No false-negative predictions were observed; an effect on RNA splicing was always predicted by these programs. In four cases (2.5%) a false-positive prediction was observed. For DNA diagnostic laboratories, these programs are therefore very useful to select intronic variants that are likely to affect RNA splicing for further analysis.
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