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 that incorporate 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. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

中文翻译：

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临床遗传变异分类的科学和技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新兴专业。该领域的持续改进对于在种系（遗传）和体细胞（肿瘤学）方面的精密医学的成功至关重要。这篇综述着重于DNA下一代测序测试的变异分类。我们首先总结了变体发现和定义方面的当前局限性，然后分别描述了主要标准和种质和体细胞测试的指导性出版物中概述的当前的五层和四层分类系统。然后，我们讨论了变体分类不一致的测量方法以及该领域对获得积极成果的偏见，以及在考虑到估计的变异分类缺陷的阳性预测值的估计范围内的小组规模和人群筛选的考虑因素。最后，我们与使用最广泛的标准和指南出版物的一些作者以及其他领域的专家分享有关变体分类当前状态的意见。《基因组学和人类遗传学年度评论》第22卷的最终最终预期发布日期是2021年8月。有关修订的估算，请参见http://www.annualreviews.org/page/journal/pubdates。