Will variants of uncertain significance still exist in 2030?
Will variants of uncertain significance still exist in 2030?
复制标题
2030年，不确定意义的变异是否仍然存在？
DOI：
10.1016/j.ajhg.2023.11.005
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发表时间：
2024
影响因子：
9.8
通讯作者：
Rehm,HeidiL
中科院分区：
文献类型：
--
作者：
Fowler,DouglasM;Rehm,HeidiL
2020年，美国国家人类基因组研究所（NHGRI）做出了十项“大胆预测”，其中包括“所有遇到的基因组变异的临床相关性都将很容易预测，从而使诊断名称'不确定意义的变异（VUS）'过时。“我们讨论了这一预测的前景，认为到2030年，编码区中的许多（如果不是大多数）VUS将得到解决。我们概述了最近的变化，使这成为可能，特别是在变异分类标准的进步，更好地利用不同类型的证据，在计算变异效应预测性能的改进，可变效应的可扩展的多重检测能够饱和的基因组，和数据共享的努力，将最大限度地从每个新的个人测序和变异解释获得的信息。我们建议临床医生和研究人员可以实现VUS在很大程度上被消除的未来，这与NHGRI的大胆预测一致。实现这一未来所需的时间长度，以及我们是否能够实现到2030年基本消除弱势群体的目标，在很大程度上取决于现在和未来几年所做的选择。我们认为，投资消除VUS是值得的，因为它们的优势仍然是精确基因组医学的最大挑战之一。
In 2020, the National Human Genome Research Institute (NHGRI) made ten "bold predictions," including that "the clinical relevance of all encountered genomic variants will be readily predictable, rendering the diagnostic designation ‘variant of uncertain significance (VUS)' obsolete." We discuss the prospects for this prediction, arguing that many, if not most, VUS in coding regions will be resolved by 2030. We outline a confluence of recent changes making this possible, especially advances in the standards for variant classification that better leverage diverse types of evidence, improvements in computational variant effect predictor performance, scalable multiplexed assays of variant effect capable of saturating the genome, and data-sharing efforts that will maximize the information gained from each new individual sequenced and variant interpreted. We suggest that clinicians and researchers can realize a future where VUSs have largely been eliminated, in line with the NHGRI's bold prediction. The length of time taken to reach this future, and thus whether we are able to achieve the goal of largely eliminating VUSs by 2030, is largely a consequence of the choices made now and in the next few years. We believe that investing in eliminating VUSs is worthwhile, since their predominance remains one of the biggest challenges to precision genomic medicine.