Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
Oncobell Program, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
Clin Chem. 2021 Mar 1;67(3):518-533. doi: 10.1093/clinchem/hvaa250.
Gene panel testing by massive parallel sequencing has increased the diagnostic yield but also the number of variants of uncertain significance. Clinical interpretation of genomic data requires expertise for each gene and disease. Heterozygous ATM pathogenic variants increase the risk of cancer, particularly breast cancer. For this reason, ATM is included in most hereditary cancer panels. It is a large gene, showing a high number of variants, most of them of uncertain significance. Hence, we initiated a collaborative effort to improve and standardize variant classification for the ATM gene.
Six independent laboratories collected information from 766 ATM variant carriers harboring 283 different variants. Data were submitted in a consensus template form, variant nomenclature and clinical information were curated, and monthly team conferences were established to review and adapt American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria to ATM, which were used to classify 50 representative variants.
Amid 283 different variants, 99 appeared more than once, 35 had differences in classification among laboratories. Refinement of ACMG/AMP criteria to ATM involved specification for twenty-one criteria and adjustment of strength for fourteen others. Afterwards, 50 variants carried by 254 index cases were classified with the established framework resulting in a consensus classification for all of them and a reduction in the number of variants of uncertain significance from 58% to 42%.
Our results highlight the relevance of data sharing and data curation by multidisciplinary experts to achieve improved variant classification that will eventually improve clinical management.
通过大规模平行测序的基因panel 检测提高了诊断率，但也增加了不确定意义的变异数量。基因组数据的临床解读需要针对每个基因和疾病的专业知识。杂合 ATM 致病性变异会增加癌症风险，尤其是乳腺癌。出于这个原因，ATM 被纳入大多数遗传性癌症panel 中。它是一个大型基因，显示出大量的变异，其中大多数具有不确定的意义。因此，我们开始合作努力，以改进和标准化 ATM 基因的变异分类。
六个独立实验室从 766 名携带 283 种不同变异的 ATM 变异携带者中收集信息。数据以共识模板的形式提交，变异命名法和临床信息进行了整理，并建立了每月团队会议，以审查和调整美国医学遗传学与基因组学学院/分子病理学协会（ACMG/AMP）标准适用于 ATM 的标准，这些标准用于分类 50 个代表性变体。
在 283 种不同的变异中，99 种出现了不止一次，35 种在不同实验室的分类中有差异。对 ATM 的 ACMG/AMP 标准的细化涉及到二十一个标准的规范和十四个其他标准的强度调整。之后，根据既定框架对 254 名索引病例携带的 50 个变体进行了分类，所有变体的分类结果一致，不确定意义的变体数量从 58%减少到 42%。
我们的结果强调了多学科专家数据共享和数据整理的重要性，以实现改进的变异分类，最终改善临床管理。
