Park Min Seon, Kumar Runjun D, Ovadiuc Cristian, Folta Andrew, McEwen Abbye E, Snyder Ashley, Villani Rehan M, Spurdle Amanda B, Fowler Douglas M, Rubin Alan F, Shirts Brian H, Starita Lea M, Stergachis Andrew B
Institute for Public Health Genetics, University of Washington, Seattle, WA, USA.
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
Am J Hum Genet. 2025 Jun 5;112(6):1468-1478. doi: 10.1016/j.ajhg.2025.04.009.
Variant-level functional data are a core component of clinical variant classification and can aid in reinterpreting variants of uncertain significance (VUSs). However, the usage of functional data by genetics professionals is currently unknown. An online survey was developed and distributed in the spring of 2024 to individuals actively engaged in variant interpretation. Quantitative and qualitative methods were used to assess responses. 190 eligible individuals responded, with 93% reporting interpreting 26 or more variants per year. The median respondent reported 11-20 years of experience. The most common professional roles were laboratory medical geneticists (23%) and variant review scientists (23%). 77% reported using functional data for variant interpretation in a clinical setting, and overall, respondents felt confident assessing functional data. However, 67% indicated that functional data for variants of interest were rarely or never available, and 91% considered insufficient quality metrics or confidence in the accuracy of data as barriers to their use. 94% of respondents noted that better access to primary functional data and standardized interpretation of functional data would improve usage. Respondents also indicated that handling conflicting functional data is a common challenge in variant interpretation that is not performed in a systematic manner across institutions. The results from this survey showed a demand for a comprehensive database with reliable quality metrics to support the use of functional evidence in clinical variant interpretation. The results also highlight a need for guidelines regarding how putatively conflicting functional data should be used for variant classification.
变异水平的功能数据是临床变异分类的核心组成部分，有助于重新解释意义未明的变异（VUS）。然而，目前尚不清楚遗传学专业人员对功能数据的使用情况。2024年春季开展了一项在线调查，并分发给积极参与变异解读的人员。采用定量和定性方法评估回复。190名符合条件的人员做出了回应，93%的人报告每年解读26个或更多变异。受访者的中位经验为11至20年。最常见的专业角色是实验室医学遗传学家（23%）和变异审查科学家（23%）。77%的人报告在临床环境中使用功能数据进行变异解读，总体而言，受访者对评估功能数据感到自信。然而，67%的人表示感兴趣的变异的功能数据很少或根本没有，91%的人认为质量指标不足或对数据准确性缺乏信心是使用这些数据的障碍。94%的受访者指出，更好地获取原始功能数据和对功能数据进行标准化解读将改善其使用情况。受访者还表示，处理相互矛盾的功能数据是变异解读中的一个常见挑战，各机构并未以系统的方式进行处理。本次调查结果显示，需要一个具有可靠质量指标的综合数据库，以支持在临床变异解读中使用功能证据。结果还凸显了需要制定关于如何将可能相互矛盾的功能数据用于变异分类的指南。
