The American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) system for variant classification is score based with five classes: benign, likely benign, variant of unknown significance (VUS), likely pathogenic, and pathogenic. Here, we present a variant classification model that can be an add-on or alternative to ACMG classification: A stepwise system that can classify any type of genetic variant (e.g., hypomorphic alleles, imprinted alleles, copy number variants, runs of homozygosity, enhancer variants, and variants related to traits). We call it the ABC system because classification is first functional (A), then clinical (B), and optionally a standard comment that fits the clinical question is selected (C). Both steps A and B have 1–5 grading when knowledge is sufficient, if not, class “zero” is assigned. Functional grading (A) only concerns biological consequences with the stages normal function (1), likely normal function (2), hypothetical functional effect (3), likely functional effect (4), and proven functional effect (5). Clinical grading (B) is genotype–phenotype focused with the stages “right type of gene” (1), risk factor (2), and pathogenic (3–5, depending on penetrance). Both grades are listed for each variant and combined to generate a joint class ranging from A to F. Importantly, the A–F classes are linked to standard comments, reflecting laboratory or national policy. In step A, the VUS class is split into class 0 (true unknown) and class 3 (hypothetical functional effect based on molecular predictions or de novo occurrence), providing a rationale for variant-of-interest reporting when the clinical picture could fit the finding. The system gives clinicians a better guide to variant significance.

美国医学遗传学和基因组学学院用于变异分类的分子病理学协会 (ACMG-AMP) 系统基于五类评分：良性、可能良性、意义不明的变异 (VUS)、可能致病和致病。在这里，我们提出了一个变异分类模型，它可以作为 ACMG 分类的附加或替代：一个逐步系统，可以对任何类型的遗传变异进行分类（例如，亚型等位基因、印记等位基因、拷贝数变异、纯合性运行、增强子变体，以及与特征相关的变体）。我们称其为 ABC 系统，因为分类首先是功能性 (A)，然后是临床性 (B)，并且可以选择适合临床问题的标准评论 (C)。当知识足够时，步骤 A 和 B 都有 1-5 分，如果没有，则分配“零”类。功能分级 (A) 仅涉及正常功能 (1)、可能的正常功能 (2)、假设的功能效应 (3)、可能的功能效应 (4) 和已证实的功能效应 (5) 阶段的生物学后果。临床分级 (B) 是基因型 - 表型，侧重于“正确的基因类型”(1)、危险因素 (2) 和致病性 (3-5，取决于外显率) 阶段。两种等级都针对每个变体列出，并组合生成一个从 A 到 F 的联合等级。重要的是，A-F 等级与标准评论相关联，反映了实验室或国家政策。在步骤 A 中，VUS 类别分为 0 类（真正未知）和 3 类（基于分子预测或从头发生的假设功能效应），当临床图片符合发现。