Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation
Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation
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DOI：
10.1136/jmg.2003.015867
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发表时间：
2004-07-01
影响因子：
4
通讯作者：
Tavtigian, SV
中科院分区：
文献类型：
--
作者：
Abkevich, V;Zharkikh, A;Tavtigian, SV
简介：对已知具有高风险易感性突变的肿瘤抑制基因（如APC、BRCA 1、BRCA 2、MLH 1、MSH 2、TP 53和PTEN）的突变筛查结果的解释正成为临床实践中越来越重要的一部分。截断突变、基因重排和明显的剪接点突变的解释通常是简单的。然而，分类的错义变体往往提出了一个困难的问题。在Myriad Genetic Laboratories进行的一系列20000个BRCA 1全序列测试中，共观察到314个不同的错义变化和8个框内缺失。在本研究之前，这些错义变化中只有21个被归类为有害或疑似有害，14个被归类为中性或临床意义不大。我们已经使用了多序列比对的orthogonal BRCA 1序列和测量的化学差异存在于序列比对中的单个残基的氨基酸之间的组合来分类错义变体和在-BRCA 1突变筛查中发现的框内缺失。结果：在本分析中，我们能够将另外50个错义突变和2个框内缺失分类为可能有害的，92个错义突变分类为可能中性的。因此，我们暂时对BRCA 1临床试验期间观察到的约50%的未分类错义变异进行了分类。讨论：分析的内部测试与我们对可能有害的变异的分类一致;然而，我们必须强调，这种分类是暂时的，没有足够的独立确认来作为临床适用的独立方法。
Introduction: Interpretation of results from mutation screening of tumour suppressor genes known to harbour high risk susceptibility mutations, such as APC, BRCA1, BRCA2, MLH1, MSH2, TP53, and PTEN, is becoming an increasingly important part of clinical practice. Interpretation of truncating mutations, gene rearrangements, and obvious splice junction mutations, is generally straightforward. However, classification of missense variants often presents a difficult problem. From a series of 20 000 full sequence tests of BRCA1 carried out at Myriad Genetic Laboratories, a total of 314 different missense changes and eight in-frame deletions were observed. Before this study, only 21 of these missense changes were classified as deleterious or suspected deleterious and 14 as neutral or of little clinical significance.Methods: We have used a combination of a multiple sequence alignment of orthologous BRCA1 sequences and a measure of the chemical difference between the amino acids present at individual residues in the sequence alignment to classify missense variants and in-frame deletions detected during mutation screening of BRCA1.Results: In the present analysis we were able to classify an additional 50 missense variants and two in-frame deletions as probably deleterious and 92 missense variants as probably neutral. Thus we have tentatively classified about 50% of the unclassified missense variants observed during clinical testing of BRCA1.Discussion: An internal test of the analysis is consistent with our classification of the variants designated probably deleterious; however, we must stress that this classification is tentative and does not have sufficient independent confirmation to serve as a clinically applicable stand alone method.