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.

跨实验室的不同致病性分类的协调对于推进临床基因组学很重要。两个由CLIA认证的电子病历和基因组学网络测序中心，六个CLIA认证的实验室以及一个在临床测序证据研究联合会中进行基因组或外显子组测序的研究实验室合作探索了当前分类不一致的来源。八个实验室各自在ACMG次要发现v.2.0基因中提交了20个分类的变体。删除重复项后，对158个变体中的每一个进行注释，并由两个其他实验室使用ACMG-AMP指南进行独立分类。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。提交的变体集包括28个P / LP变体，96个VUS和34个LB / B变体，主要是癌症（40％）和心脏（27％）风险基因。八十六种（54％）变体达到了五类完全一致（即P，LP，VUS，LB，B），并且有17种（11％）的不一致性可能影响临床推荐（P / LP与VUS / LB / B）。以P和LP提交的变体中，分别有21％和63％与VUS不符。在经过进一步审查的54个原始不协调变体中，有32个达成了共识，审查后一致性率为84％（118/140个变体）。该项目提供了变体一致性的最新估计，确定了LP分类变体的考虑因素，并突出了当前的不一致性来源。实验室之间不断增加变体分类和证据的共享，