Development of recommendations and policies for genetic variant reclassification

项目摘要 随着基因组序列数据的产生速度更快，成本更低，最重要的是 目前临床基因检测面临的挑战是变异分类。目前，有标记的 不同临床实验室间变异分类的差异，具有临床意义 29%的变异有不一致的解释。以前被归类为 现在已知致病是良性的，因为越来越多的种族多样性 参考数据，而这一问题在非欧洲血统的个人中更为常见。在… 与此同时，相当大比例的变异被归类为具有未知意义 (VUS)，没有足够的数据来证明或反驳与医学上的致病关联 条件。然而，在解释基因组数据方面的进展将导致就如何解释基因组数据达成更大的共识 调用当前受到不一致分类的变体，会出现以下问题 关于变异重新分类信息将如何到达患者和他们的医疗保健 供应商。目前还没有来自专业组织或意见的明确指导 领导者关于如何处理不同的重新分类，而该领域似乎不确定如何 请回答。包括实验室、提供者、患者和付款人在内的利益相关者可能有不同的 观点和观点。为这场关键的讨论提供经验基础，并 为制定实地指导，我们将开展一系列活动，包括重点小组和 对3个关键的利益相关者群体进行在线调查：患者、提供者和实验室。我们会 有三个工作组来定义要考虑的法律、道德和经济方面，并 制定可行的解决方案。我们将主办一次与遗传学、临床专家的年度会议 实验室运营、报销、健康经济学家、监管和法律问题以及道德问题， 与临床医生和患者倡导者一起，为项目提供指导，审查数据 并制定一套备选方案和最后一套建议来解决这一问题。我们会 通过在线调查征求利益相关者对可能的解决方案的意见，并得出最终结论 我们将向基因组学社区和美国人委员会提交建议 医学遗传学和基因组学学院指导采用可接受的和 对这一快速变化领域负责任的政策。

Project Abstract As genomic sequence data are being produced faster and at lower cost, the most significant challenge in clinical genetic testing today is variant classification. Currently, there are marked differences in variant classification among clinical laboratories, with clinically significant discrepancies in 29% of variants interpreted. Variants that were previously categorized as pathogenic are now known to be benign with the increasing availability of more ethnically diverse reference data, and this is issue is more common for individuals of non-European ancestry. At the same time, a substantial percentage of variants are classified as of unknown significance (VUS), with inadequate data to prove or disprove a pathogenic association with a medical condition. Progress in interpreting genomic data, however, will lead to greater agreement on how to call variants that are currently subject to discrepant classifications and the question arises about how will that information about reclassification of variants reach patients and their health care providers. There is currently no definitive guidance from professional organizations or opinion leaders about how to handle variant reclassification, and the field seems uncertain how to respond. Stakeholders including laboratories, providers, patients, and payers likely have different perspectives and opinions. To provide an empirical foundation for this critical discussion and develop guidance for the field, we will conduct a series of activities including focus groups and online surveys with 3 key stakeholder groups: patients, providers, and the laboratories. We will have three working groups to define the legal, ethical, and economic aspects to consider and develop possible solutions. We will host an annual meeting with experts on genetics, clinical laboratory operations, reimbursement, health economists, regulatory and legal issues, and ethics, along with clinicians and patient advocates, to provide guidance for the project, to review the data and develop a set of options and a final set of recommendations to address this issue. We will seek input on possible solutions from stakeholders through an online survey and arrive at final recommendations that we will present to the genomics community and to board of the American College of Medical Genetics and Genomics to guide the adoption of an acceptable and responsible policy in for this rapidly changing area.