遗传变异分类标准与指南

免责声明

These ACMG Standards and Guidelines were developed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory services. Adherence to these standards and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient’s record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular guideline was adopted and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.

ACMG制定的标准与指南作为教育资源旨在帮助临床遗传学家提供优质的临床检验服务。遵循该标准和指南属于自愿行为并且不一定能够确保一个成功的医疗结局。该标准和指南并不囊括所有合适的流程和检测，也不排斥其他可以获得相同结果的流程和检测。临床实验室遗传学家应该利用自己的专业知识，依据病人或样本的具体情况来判断某一具体的流程或检测的合理性。我们鼓励临床实验室遗传学家记录对病人使用的某一具体流程或检测的原理，不管这个原理与这些标准与指南是否符合。同时建议临床实验室遗传学家关注指南的采用时间，应考虑到此后更新的一些相关医疗和科学信息。还需谨慎考虑到知识产权可能会限制某些检测或流程的使用。

摘要

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes, and epigenetic assays for genetic disorders. By virtue of increased complexity, this shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context the ACMG convened a workgroup in 2013 comprising representatives from the ACMG, the Association for Molecular Pathology (AMP), and the College of American Pathologists to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP, and College of American Pathologists stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. This report recommends the use of specific standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified in genes that cause Mendelian disorders. Moreover, this recommendation describes a process for classifying variants into these five categories based on criteria using typical types of variant evidence (e.g., population data, computational data, functional data, segregation data). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a Clinical Laboratory Improvement Amendments–approved laboratory, with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or the equivalent.

美国医学遗传学与基因组学学会(The American College of Medical Genetics and Genomics，ACMG)曾制定过序列变异解读指南。在过去的十年中，随着新一代高通量测序的出现，测序技术有了快速发展。利用新一代测序技术，临床实验室检测遗传性疾病的产品种类不断增加，包括基因分型、单基因、基因包、外显子组、基因组、转录组和表观遗传学检测。随着技术的复杂性日益增加，基因检测在序列解读方面不断面临着新的挑战。因此ACMG在2013年成立了一个工作组来重新审视和修订序列变异解读的标准和指南，工作组包括ACMG、分子病理协会(the Association for Molecular Pathology，AMP)和美国病理学家协会(the College of American Pathologists，CAP)的代表。该工作组由临床实验室主任和临床医生组成。本报告代表了工作组中来自ACMG，AMP和CAP的专家意见。本报告提出的建议可应用于临床实验室的各种基因检测方法，包括基因分型、单基因、基因包、外显子组和基因组。本报告建议使用特定标准术语来描述孟德尔疾病相关的基因变异——“致病的”、“可能致病的”、“意义不明确的”、“可能良性的”和“良性的”。此外，本报告描述了基于典型的数据类型(如人群数据，计算数据，功能数据，共分离数据)对变异进行五级分类的标准过程。由于临床基因检测分析和解读中不断增加的复杂性，ACMG强烈建议临床分子基因检测应在符合临床实验室改进修正案(CLIA)认证的实验室中进行，其检测结果应由通过职业认证的临床分子遗传学家或分子遗传病理学家或相同职能的专业人员解读。

Key Words 关键词

ACMG laboratory guideline; clinical genetic testing; interpretation; reporting; sequence variant terminology; variant reporting

ACMG实验室指南；临床遗传检测；解读；报告；序列变异术语；变异报告