Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework
Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework
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DOI：
10.1186/s13073-019-0690-2
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发表时间：
2019-12-31
期刊：
影响因子：
12.3
通讯作者：
Topper, Scott
中科院分区：
文献类型：
--
作者：
Brnich, Sarah E.;Abou Tayoun, Ahmad N.;Topper, Scott
背景美国医学遗传学和基因组学学会（ACMG）/分子病理学协会（AMP）临床变异解释指南为不同类型的证据建立了标准。这包括用于“完善的”功能测定的强有力的证据代码PS3和BS 3，其分别证明变体具有异常或正常的基因/蛋白质功能。然而，他们没有提供关于如何评价功能证据的详细指南，并且PS3/BS 3代码应用的差异是导致实验室之间变异解释不一致的原因。本建议旨在提供一种更结构化的方法，用于评估功能检测试剂盒的变异解读，并指导基于检测试剂盒验证使用不同水平的强度。方法临床基因组资源（ClinGen）序列变异解释（SVI）工作组使用来自ClinGen变异形成专家小组的策划功能证据-制定规则规范和专家意见，通过多次面对面和虚拟会议完善PS3/BS 3标准。我们使用不同数量的变异对照品估计了试验的致病性几率，以确定达到中等水平证据所需的最低对照品。ClinGen指导委员会和外部专家的反馈被纳入多个开发阶段的建议中。结果SVI工作组为评估者制定了关于功能数据临床有效性评估的建议，并制定了一个四步临时框架，以确定可用于临床变异解释的适当证据强度。这些步骤如下：（1）定义疾病机制，（2）评价该领域使用的一般类别测定的适用性，（3）评价测定的特定实例的有效性，以及（4）将证据应用于个体变异解释。我们发现，在缺乏严格统计分析的情况下，至少需要11个致病性和良性变异对照才能达到中等水平的证据。结论这里所描述的功能性证据评价的建议和方法应该有助于阐明功能性检测的临床变异解释过程。此外，我们希望这些建议将有助于与基础科学家建立富有成效的伙伴关系，这些基础科学家已经开发出用于询问各种基因功能的功能测定法。
Background The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) clinical variant interpretation guidelines established criteria for different types of evidence. This includes the strong evidence codes PS3 and BS3 for "well-established" functional assays demonstrating a variant has abnormal or normal gene/protein function, respectively. However, they did not provide detailed guidance on how functional evidence should be evaluated, and differences in the application of the PS3/BS3 codes are a contributor to variant interpretation discordance between laboratories. This recommendation seeks to provide a more structured approach to the assessment of functional assays for variant interpretation and guidance on the use of various levels of strength based on assay validation. Methods The Clinical Genome Resource (ClinGen) Sequence Variant Interpretation (SVI) Working Group used curated functional evidence from ClinGen Variant Curation Expert Panel-developed rule specifications and expert opinions to refine the PS3/BS3 criteria over multiple in-person and virtual meetings. We estimated the odds of pathogenicity for assays using various numbers of variant controls to determine the minimum controls required to reach moderate level evidence. Feedback from the ClinGen Steering Committee and outside experts were incorporated into the recommendations at multiple stages of development. Results The SVI Working Group developed recommendations for evaluators regarding the assessment of the clinical validity of functional data and a four-step provisional framework to determine the appropriate strength of evidence that can be applied in clinical variant interpretation. These steps are as follows: (1) define the disease mechanism, (2) evaluate the applicability of general classes of assays used in the field, (3) evaluate the validity of specific instances of assays, and (4) apply evidence to individual variant interpretation. We found that a minimum of 11 total pathogenic and benign variant controls are required to reach moderate-level evidence in the absence of rigorous statistical analysis. Conclusions The recommendations and approach to functional evidence evaluation described here should help clarify the clinical variant interpretation process for functional assays. Further, we hope that these recommendations will help develop productive partnerships with basic scientists who have developed functional assays that are useful for interrogating the function of a variety of genes.