Rosenthal E T, Bowles K R, Pruss D, van Kan A, Vail P J, McElroy H, Wenstrup R J
Myriad Genetic Laboratories, Inc., Salt Lake City, UT, USA.
Clin Genet. 2015 Dec;88(6):533-41. doi: 10.1111/cge.12560. Epub 2015 Feb 11.
Based on current consensus guidelines and standard practice, many genetic variants detected in clinical testing are classified as disease causing based on their predicted impact on the normal expression or function of the gene in the absence of additional data. However, our laboratory has identified a subset of such variants in hereditary cancer genes for which compelling contradictory evidence emerged after the initial evaluation following the first observation of the variant. Three representative examples of variants in BRCA1, BRCA2 and MSH2 that are predicted to disrupt splicing, prematurely truncate the protein, or remove the start codon were evaluated for pathogenicity by analyzing clinical data with multiple classification algorithms. Available clinical data for all three variants contradicts the expected pathogenic classification. These variants illustrate potential pitfalls associated with standard approaches to variant classification as well as the challenges associated with monitoring data, updating classifications, and reporting potentially contradictory interpretations to the clinicians responsible for translating test outcomes to appropriate clinical action. It is important to address these challenges now as the model for clinical testing moves toward the use of large multi-gene panels and whole exome/genome analysis, which will dramatically increase the number of genetic variants identified.
根据当前的共识指南和标准做法，在临床检测中检测到的许多基因变异，在没有其他数据的情况下，根据其对基因正常表达或功能的预测影响，被归类为致病基因变异。然而，我们实验室在遗传性癌症基因中发现了这类变异的一个子集，在首次观察到该变异后的初步评估后，出现了令人信服的矛盾证据。通过使用多种分类算法分析临床数据，对BRCA1、BRCA2和MSH2中预测会破坏剪接、使蛋白质过早截短或去除起始密码子的变异的三个代表性例子进行了致病性评估。所有这三个变异的现有临床数据都与预期的致病分类相矛盾。这些变异说明了与变异分类的标准方法相关的潜在陷阱，以及与监测数据、更新分类以及向负责将检测结果转化为适当临床行动的临床医生报告潜在矛盾解释相关的挑战。随着临床检测模式转向使用大型多基因检测板和全外显子组/基因组分析，这将大幅增加所识别的基因变异数量，现在应对这些挑战非常重要。
