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The Science and Art of Clinical Genetic Variant Classification and Its Impact on Test Accuracy
Annual Review of Genomics and Human Genetics ( IF 7.7 ) Pub Date : 2021-08-31 , DOI: 10.1146/annurev-genom-121620-082709
Hunter H Giles 1 , Madhuri R Hegde 2, 3 , Elaine Lyon 4 , Christine M Stanley 5, 6 , Iain D Kerr 7 , Megan E Garlapow 1 , Julie M Eggington 1
Affiliation  

Clinical genetic variant classification science is a growing subspecialty of clinical genetics and genomics. The field's continued improvement is essential for the success of precision medicine in both germline (hereditary) and somatic (oncology) contexts. This review focuses on variant classification for DNA next-generation sequencing tests. We first summarize current limitations in variant discovery and definition, and then describe the current five- and four-tier classification systems outlined in dominant standards and guideline publications for germline and somatic tests, respectively. We then discuss measures of variant classification discordance and the field's bias for positive results, as well as considerations for panel size and population screening in the context of estimates of positive predictive value thatincorporate estimated variant classification imperfections. Finally, we share opinions on the current state of variant classification from some of the authors of the most widely used standards and guideline publications and from other domain experts.

中文翻译:


临床遗传变异分类的科学和艺术及其对测试准确性的影响

临床遗传变异分类科学是临床遗传学和基因组学的一个不断发展的亚专业。该领域的持续改进对于精确医学在生殖系(遗传)和体细胞(肿瘤学)环境中的成功至关重要。本综述侧重于 DNA 下一代测序测试的变异分类。我们首先总结了当前变异发现和定义的局限性,然后分别描述了主要标准和指南出版物中概述的当前五级和四级分类系统,分别用于种系和体细胞测试。然后我们讨论变量分类不一致的度量和该领域对积极结果的偏见,以及在包含估计的变异分类缺陷的阳性预测值估计值的背景下对面板大小和群体筛选的考虑。最后,我们分享了一些最广泛使用的标准和指南出版物的作者以及其他领域专家对变体分类现状的看法。

更新日期:2021-09-01
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