Tesoriero A A, Wong E M, Jenkins M A, Hopper J L, Brown M A, Chenevix-Trench G, Spurdle A B, Southey M C
Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Victoria, Australia.
Hum Mutat. 2005 Nov;26(5):495. doi: 10.1002/humu.9379.
Genetic screening of women from multiple-case breast cancer families and other research-based endeavors have identified an extensive collection of germline variations of BRCA1 and BRCA2 that can be classified as deleterious and have clinical relevance. For some variants, such as those in the conserved intronic splice site regions which are highly likely to alter splicing, it is not possible to classify them based on the identified DNA sequence variation alone. We studied 11 multiple-case breast cancer families carrying seven distinct splice site region genetic alterations in BRCA1 or BRCA2 (BRCA1, c.IVS6-2delA, c.IVS9-2A>C, c.IVS4-1G>T, c.IVS20+1G>A and BRCA2, c.IVS17-1G>C, c.IVS20+1G>A, c.IVS7-1G>A) and applied SpliceSiteFinder to predict possible changes in efficiency of splice donor and acceptor sites, characterized the transcripts, and estimated the average age-specific cumulative risk (penetrance) using a modified segregation analysis. SpliceSiteFinder predicted and we identified transcipts that illustrated that all variants caused exon skipping, and all but two led to frameshifts. The risks of breast cancer to age 70 yrs, averaged over all variants, over BRCA1 variants alone, and over BRCA2 variants alone, were 73% (95% confidence interval 47-93), 64% (95%CI 28-96) and 79% (95%CI 48-98) respectively (all P<0.0001). Therefore five of these seven consensus splice site variants of BRCA1 and BRCA2 produce a transcript similar to that of other previously described deleterious exonic variants and are associated with similar high lifetime risks.
对来自多例乳腺癌家族的女性进行基因筛查以及其他基于研究的工作，已经鉴定出大量可归类为有害且具有临床相关性的BRCA1和BRCA2种系变异。对于某些变异，例如那些位于保守内含子剪接位点区域、极有可能改变剪接的变异，仅根据已识别的DNA序列变异无法对其进行分类。我们研究了11个携带BRCA1或BRCA2中7种不同剪接位点区域基因改变的多例乳腺癌家族（BRCA1，c.IVS6 - 2delA、c.IVS9 - 2A>C、c.IVS4 - 1G>T、c.IVS20 + 1G>A；BRCA2，c.IVS17 - 1G>C、c.IVS20 + 1G>A、c.IVS7 - 1G>A），应用剪接位点查找工具预测剪接供体和受体位点效率的可能变化，对转录本进行特征分析，并使用改良的分离分析估计特定年龄的平均累积风险（外显率）。剪接位点查找工具进行了预测，我们也鉴定出了转录本，结果表明所有变异均导致外显子跳跃，除两个变异外均导致移码。在所有变异、仅BRCA1变异以及仅BRCA2变异的情况下，至70岁时的乳腺癌风险分别为73%（95%置信区间47 - 93）、64%（95%CI 28 - 96）和79%（95%CI 48 - 98）（所有P<0.0001）。因此，BRCA1和BRCA2的这7种共有剪接位点变异中的5种产生的转录本与其他先前描述的有害外显子变异相似，并且具有相似的高终生风险。
