Universität zu Köln

Houge, Gunnar, Laner, Andreas, Cirak, Sebahattin, de Leeuw, Nicole, Scheffer, Hans and den Dunnen, Johan T. (2022). Stepwise ABC system for classification of any type of genetic variant. Eur. J. Hum. Genet., 30 (2). S. 150 - 160. LONDON: SPRINGERNATURE. ISSN 1476-5438

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Houge, Gunnar UNSPECIFIED UNSPECIFIED UNSPECIFIED Laner, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Cirak, Sebahattin UNSPECIFIED UNSPECIFIED UNSPECIFIED de Leeuw, Nicole UNSPECIFIED UNSPECIFIED UNSPECIFIED Scheffer, Hans UNSPECIFIED UNSPECIFIED UNSPECIFIED den Dunnen, Johan T. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-593605
DOI:	10.1038/s41431-021-00903-z
Journal or Publication Title:	Eur. J. Hum. Genet.
Volume:	30
Number:	2
Page Range:	S. 150 - 160
Date:	2022
Publisher:	SPRINGERNATURE
Place of Publication:	LONDON
ISSN:	1476-5438
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language JOINT CONSENSUS RECOMMENDATION; INTERPRETATION GUIDELINES; MEDICAL GENETICS; AMERICAN-COLLEGE; ACMG; STANDARDS; LABORATORIES; GENOMICS Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59360