Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing.
Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing.
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DOI：
10.1200/jco.2016.68.4316
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发表时间：
2016-12
期刊：
影响因子：
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通讯作者：
Domchek SM
中科院分区：
文献类型：
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作者：
Balmaña J;Digiovanni L;Gaddam P;Walsh MF;Joseph V;Stadler ZK;Nathanson KL;Garber JE;Couch FJ;Offit K;Robson ME;Domchek SM
大规模平行测序允许同时测试与癌症易感性相关的多个基因。变体分类指南；然而，实验室和提供者对这些准则的解释可能不同，导致相互矛盾的报告，并可能导致不适当的医疗管理。我们描述了临床实验室改进修正案批准的商业临床实验室之间相互冲突的变体解释，这些解释报告给了多元检测前瞻性注册中心（PROMPT），一个在线遗传注册中心。2014年9月至2015年10月期间，该研究收集了1191名接受遗传癌症易感性测试的个体的临床数据和基因检测结果。总体而言，518名参与者（603个遗传变异）的结果被多个实验室解释，包括至少一个提交给ClinVar的实验室，这些被用作当前分析的最终队列。在603个变异中，221个（37%）被分类为不确定意义的变异（VUS）， 191个（32%）被分类为致病性变异，34个（6%）被分类为良性变异。155个（26%）报告实验室的解释存在差异。最常报道的相互矛盾的解释是CHEK2和ATM，其次是RAD51C、PALB2、BARD1、NBN和BRIP1。在所有参与者中，518人中有56人（11%）的变异具有相互矛盾的解释，从致病性/可能致病性到VUS，这种差异可能改变医疗管理。临床实践中使用的多重面板测试对基因发现的相互矛盾的解释是经常发生的，并且可能对医疗管理决策产生影响。
Massively parallel sequencing allows simultaneous testing of multiple genes associated with cancer susceptibility. Guidelines are available for variant classification; however, interpretation of these guidelines by laboratories and providers may differ and lead to conflicting reporting and, potentially, to inappropriate medical management. We describe conflicting variant interpretations between Clinical Laboratory Improvement Amendments–approved commercial clinical laboratories, as reported to the Prospective Registry of Multiplex Testing (PROMPT), an online genetic registry. Clinical data and genetic testing results were gathered from 1,191 individuals tested for inherited cancer susceptibility and self-enrolled in PROMPT between September 2014 and October 2015. Overall, 518 participants (603 genetic variants) had a result interpreted by more than one laboratory, including at least one submitted to ClinVar, and these were used as the final cohort for the current analysis. Of the 603 variants, 221 (37%) were classified as a variant of uncertain significance (VUS), 191 (32%) as pathogenic, and 34 (6%) as benign. The interpretation differed among reporting laboratories for 155 (26%). Conflicting interpretations were most frequently reported for CHEK2 and ATM, followed by RAD51C, PALB2, BARD1, NBN, and BRIP1. Among all participants, 56 of 518 (11%) had a variant with conflicting interpretations ranging from pathogenic/likely pathogenic to VUS, a discrepancy that may alter medical management. Conflicting interpretation of genetic findings from multiplex panel testing used in clinical practice is frequent and may have implications for medical management decisions.