Development of recommendations and policies for genetic variant reclassification

项目摘要 随着基因组序列数据以更快和更低的成本产生， 当今临床基因检测的挑战是变异分类。目前，有标记 临床实验室之间的变异分类差异，具有临床意义 29%的变异被解释。之前被归类为 致病性现在已知是良性的，随着越来越多的种族多样化的可用性， 参考数据，这个问题在非欧洲血统的个体中更常见。在 与此同时，相当大比例的变异被归类为意义不明 (VUS)，没有足够的数据证明或反驳与医学相关的致病性 条件然而，在解释基因组数据方面取得的进展将导致在以下方面达成更大的一致： 调用目前受差异分类影响的变体， 关于变异重新分类信息如何到达患者和他们的健康护理 提供商目前还没有来自专业机构或意见的明确指导 领导人关于如何处理变异重新分类，该领域似乎不确定如何 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 观点和意见。为这一批判性讨论提供一个经验基础， 为制定该领域的指导方针，我们将开展一系列活动，包括焦点小组， 与3个主要利益相关者群体进行在线调查：患者、提供者和实验室。我们将 有三个工作组来确定需要考虑的法律的、道德的和经济的方面， 制定可能的解决方案。我们将举办一次年会，邀请遗传学、临床 实验室操作、报销、卫生经济学家、监管和法律的问题以及伦理， 沿着与临床医生和病人的倡导者，为项目提供指导，审查数据 并制定一套备选方案和一套最终建议来解决这一问题。我们将 通过在线调查征求利益攸关方对可能解决方案的意见， 我们将向基因组学界和美国生物技术委员会提出建议， 医学遗传学和基因组学学院，以指导通过一个可接受的， 在这个快速变化的领域，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.