Variant Classification Concordance using the ACMG-AMP Variant Interpretation Guidelines across Nine Genomic Implementation Research Studies
Variant Classification Concordance using the ACMG-AMP Variant Interpretation Guidelines across Nine Genomic Implementation Research Studies
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DOI：
10.1016/j.ajhg.2020.09.011
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发表时间：
2020-11-05
影响因子：
9.8
通讯作者：
Jarvik, Gail P.
中科院分区：
文献类型：
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作者：
Amendola, Laura M.;Muenzen, Kathleen;Jarvik, Gail P.
实验室间变异致病分类的协调对于推进临床基因组学很重要。在临床测序证据生成研究联盟中，两个经CLIA认证的电子医疗记录和基因组网络测序中心和六个经CLIA认证的实验室和一个执行基因组或外显子组测序的研究实验室合作，探索当前分类不一致的来源。八个实验室分别提交了ACMG二次发现v.2.0基因的20个分类变体。去除重复后，另外两个实验室根据ACMG-AMP指南对158个变体进行了注释和独立分类。评估了三个实验室的总体一致性，并通过电话会议和电子邮件审查了不一致的变体。提交的变异组包括28个P/LP变异体、96个VUS变异体和34个LB/B变异体，主要涉及癌症(40%)和心脏(27%)危险基因。86个(54%)变异达到完全五类(即P、LP、VUS、LB、B)的一致性，17个(11%)的不一致可能影响临床推荐(P/LP与VUS/LB/B)。P和LP分别有21%和63%的变异与VUS不一致。在接受进一步审查的54个最初不一致的变体中，32个达成一致，审查后的符合率为84%(118/140个变体)。本项目提供了对变异一致性的最新估计，确定了LP分类变异的考虑因素，并突出了持续存在的不一致性来源。在实验室之间继续和增加不同分类和证据的共享，以及克林根正在进行的提供一般以及针对基因和疾病的指导的工作，将导致一致性的持续增加。
Harmonization of variant pathogenicity classification across laboratories is important for advancing clinical genomics. The two CLIA-accredited Electronic Medical Record and Genomics Network sequencing centers and the six CLIA-accredited laboratories and one research laboratory performing genome or exome sequencing in the Clinical Sequencing Evidence-Generating Research Consortium collaborated to explore current sources of discordance in classification. Eight laboratories each submitted 20 classified variants in the ACMG secondary finding v.2.0 genes. After removing duplicates, each of the 158 variants was annotated and independently classified by two additional laboratories using the ACMG-AMP guidelines. Overall concordance across three laboratories was assessed and discordant variants were reviewed via teleconference and email. The submitted variant set included 28 P/LP variants, 96 VUS, and 34 LB/B variants, mostly in cancer (40%) and cardiac (27%) risk genes. Eighty-six (54%) variants reached complete five-category (i.e., P, LP, VUS, LB, B) concordance, and 17 (11%) had a discordance that could affect clinical recommendations (P/LP versus VUS/LB/B). 21% and 63% of variants submitted as P and LP, respectively, were discordant with VUS. Of the 54 originally discordant variants that underwent further review, 32 reached agreement, for a post-review concordance rate of 84% (118/140 variants). This project provides an updated estimate of variant concordance, identifies considerations for LP classified variants, and highlights ongoing sources of discordance. Continued and increased sharing of variant classifications and evidence across laboratories, and the ongoing work of ClinGen to provide general as well as gene- and disease-specific guidance, will lead to continued increases in concordance.