Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium
Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium
复制标题
DOI：
10.1016/j.ajhg.2016.03.024
复制
发表时间：
2016-06-02
影响因子：
9.8
通讯作者：
Rehm, Heidi L.
中科院分区：
文献类型：
--
作者：
Amendola, Laura M.;Jarvik, Gail P.;Rehm, Heidi L.
鉴于实验室考虑的遗传证据种类繁多，评估变异的致病性具有挑战性。决定如何权衡每种类型的证据是困难的，需要标准。2015年，美国医学遗传学和基因组学学院（ACMG）和分子病理学协会（AMP）发布了评估孟德尔疾病相关基因变异的指南。参与临床测序探索性研究（CSER）联盟的9个分子诊断实验室对99种变异进行了这些指南的试点，这些变异涵盖了所有类别（致病性、可能致病性、不确定意义、可能良性和良性）。9种变体分发给所有实验室，其余90种由3个实验室进行评价。实验室通过使用实验室自己的方法和ACMG-AMP标准对每个变体进行分类。实验室内使用的两种方法之间的一致性较高（K-alpha = 0.91），一致性为79%。然而，在实验室之间，任一分类系统的一致性仅为34%。在对ACMG=AMP标准进行共识讨论和详细审查后，一致性增加到71%。确定了ACMG-AMP分类中最初不一致的原因，并提出了澄清和增加ACMG-AMP标准规范的建议。总之，尽管ACMG-AMP指南的初始试点并未导致变异解释的一致性增加，但比较变异解释以识别差异并具有共同框架以促进解决这些差异有利于提高一致性，允许迭代运动以提高与单基因疾病相关的基因中变异的报告一致性。
Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider. Deciding how to weigh each type of evidence is difficult, and standards have been needed. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases. Nine molecular diagnostic laboratories involved in the Clinical Sequencing Exploratory Research (CSER) consortium piloted these guidelines on 99 variants spanning all categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign). Nine variants were distributed to all laboratories, and the remaining 90 were evaluated by three laboratories. The laboratories classified each variant by using both the laboratory's own method and the ACMG-AMP criteria. The agreement between the two methods used within laboratories was high (K-alpha = 0.91) with 79% concordance. However, there was only 34% concordance for either classification system across laboratories. After consensus discussions and detailed review of the ACMG=AMP criteria, concordance increased to 71%. Causes of initial discordance in ACMG-AMP classifications were identified, and recommendations on clarification and increased specification of the ACMG-AMP criteria were made. In summary, although an initial pilot of the ACMG-AMP guidelines did not lead to increased concordance in variant interpretation, comparing variant interpretations to identify differences and having a common framework to facilitate resolution of those differences were beneficial for improving agreement, allowing iterative movement toward increased reporting consistency for variants in genes associated with monogenic disease.