期刊
HUMAN MUTATION
卷 31, 期 6, 页码 E1484-E1505出版社
WILEY
DOI: 10.1002/humu.21267
关键词
BRCA1; BRCA2; clinical significance; variants; splicing
资金
- NHMRC [145684, 288704, 454508, ID442970]
- National Breast Cancer Foundation
- Queensland Cancer Fund
- Cancer Councils of New South Wales, Victoria, Tasmania and South Australia
- Cancer Foundation of Western Australia
- QIMR Higher Degrees Committee
- Ludwig Institute for Cancer Research
- Canadian Institute for Health Research
- NIH [CA116167]
- Breast Cancer specialized Program in research Excellence [P50 CA116201]
- American Cancer Society [RSG-04-220-01-CCE]
- NATIONAL CANCER INSTITUTE [R01CA116167, P50CA116201] Funding Source: NIH RePORTER
Missense substitutions in high-risk cancer susceptibility genes create clinical uncertainty in the genetic counseling process. Multifactorial likelihood classification approaches and in vitro assays are useful for the classification of exonic sequence variants in BRCA1 and BRCA2, but these currently rely on the assumption that changes in protein function are the major biological mechanism of pathogenicity. This study investigates the potentially pathogenic role of aberrant splicing for exonic variants predicted to encode missense substitutions using patient-derived RNA. No splicing aberrations were identified for BRCA1c.5054C>T and BRCA2c.7336A>G, c.8839G>A, and c.9154C>T. However, RT-PCR analysis identified a major splicing aberration for BRCA1c.4868C>G(p.Ala1623Gly), a variant encoding a missense substitution considered likely to be neutral. Splicing aberrations were also observed for BRCA2c.7988A>T(p.Glu2663Val) and c.8168A>G(p.Asp2723Gly), but both variant and wildtype alleles were shown to be present in full-length mRNA transcripts, suggesting that variant protein may be translated. BRCA2 protein function assays indicated that BRCA2p.Glu2663Val, p.Asp2723Gly and p.Arg3052Trp missense proteins have abrogated function consistent with pathogenicity. Multifactorial likelihood analysis provided evidence for pathogenicity for BRCA1 c.5054C>T(p.Thr1685Ile) and BRCA2c.7988A>T(p.Glu2663Val), c.8168A>G(p.Asp2723Gly) and c.9154C>T(p.Arg3052Trp), supporting experimentally derived evidence. These findings highlight the need for improved bioinformatic prediction of splicing aberrations and to refine multifactorial likelihood models used to assess clinical significance. (C) 2010 Wiley-Liss, Inc.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据