Stepwise ABC system for classification of any type of genetic variant

42Citations
Citations of this article
122Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

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.

Cite

CITATION STYLE

APA

Houge, G., Laner, A., Cirak, S., de Leeuw, N., Scheffer, H., & den Dunnen, J. T. (2022). Stepwise ABC system for classification of any type of genetic variant. European Journal of Human Genetics, 30(2), 150–159. https://doi.org/10.1038/s41431-021-00903-z

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free