Next-generation sequencing has had a significant impact on genetic disease diagnosis, but the interpretation of the vast amount of genomic data it generates can be challenging. To address this, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology have established guidelines for standardized variant interpretation. In this manuscript, we present the updated Hospital Israelita Albert Einstein Standards for Constitutional Sequence Variants Classification, incorporating modifications from leading genetics societies and the ClinGen initiative. First, we standardized the scientific publications, documents, and other reliable sources for this document to ensure an evidence-based approach. Next, we defined the databases that would provide variant information for the classification process, established the terminology for molecular findings, set standards for disease-gene associations, and determined the nomenclature for classification criteria. Subsequently, we defined the general rules for variant classification and the Bayesian statistical reasoning principles to enhance this process. We also defined bioinformatics standards for automated classification. Our workgroup adhered to gene-specific rules and workflows curated by the ClinGen Variant Curation Expert Panels whenever available. Additionally, a distinct set of specifications for criteria modulation was created for cancer genes, recognizing their unique characteristics. The development of an internal consensus and standards for constitutional sequence variant classification, specifically adapted to the Brazilian population, further contributes to the continuous refinement of variant classification practices. The aim of these efforts from the workgroup is to enhance the reliability and uniformity of variant classification.

中文翻译：

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Israelita Albert Einstein 医院宪法序列变异分类标准：2023 版

下一代测序对遗传病诊断产生了重大影响，但对其生成的大量基因组数据的解释可能具有挑战性。为了解决这个问题，美国医学遗传学和基因组学学院以及分子病理学协会制定了标准化变异解释指南。在这份手稿中，我们介绍了更新的以色列医院阿尔伯特·爱因斯坦宪法序列变异分类标准，其中纳入了领先遗传学协会和 ClinGen 倡议的修改。首先，我们对本文件的科学出版物、文件和其他可靠来源进行了标准化，以确保采用基于证据的方法。接下来，我们定义了为分类过程提供变异信息的数据库，建立了分子发现的术语，设定了疾病基因关联的标准，并确定了分类标准的术语。随后，我们定义了变量分类的一般规则和贝叶斯统计推理原则来增强这一过程。我们还定义了自动分类的生物信息学标准。我们的工作组遵守 ClinGen 变异管理专家小组制定的基因特定规则和工作流程（只要有）。此外，还为癌症基因创建了一套独特的标准调节规范，认识到其独特的特征。制定专门适合巴西人群的宪法序列变异分类的内部共识和标准，进一步有助于变异分类实践的不断完善。工作组这些努力的目的是提高变体分类的可靠性和一致性。