Comparison of the ABC and ACMG systems for variant classification
Gunnar Houge, Eirik Bratland, Ingvild Aukrust, Kristian Tveten, Gabrielė Žukauskaitė, Ivona Sansović, Alejandro Brea‐Fernández, Karin Mayer, Teija Paakkola, Caoimhe McKenna, William D. Wright, Milica Keckarević Marković, Dorte L. Lildballe, M Konečný, Thomas Smol, Pia Alhopuro, Estelle Arnaud Gouttenoire, Katharina Obeid, Албена Тодорова, Milena Janković, Joanna M. Lubieniecka, Maja Stojiljković, Marie‐Pierre Buisine, Bjørn Ivar Haukanes, Marie Lorans, Hanno Roomere, François Petit, Maria K. Haanpää, Claire Bénéteau, Belén Pérez, Dijana Plaseska‐Karanfilska, Matthias Rath, Nico Fuhrmann, Bibiana I. Ferreira, Coralea Stephanou, Wenche Sjursen, Aleš Maver, Cécile Rouzier, Adela Chiriță-Emandi, João Gonçalves, Wei Cheng David Kuek, Martin Broly, Lonneke Haer‐Wigman, Meow‐Keong Thong, Sok-Kun Tae, Michaela Hýblová, Johan T. den Dunnen, Andreas Laner
Abstract
The ABC and ACMG variant classification systems were compared by asking mainly European clinical laboratories to classify variants in 10 challenging cases using both systems, and to state if the variant in question would be reported as a relevant result or not as a measure of clinical utility. In contrast to the ABC system, the ACMG system was not made to guide variant reporting but to determine the likelihood of pathogenicity. Nevertheless, this comparison is justified since the ACMG class determines variant reporting in many laboratories. Forty-three laboratories participated in the survey. In seven cases, the classification system used did not influence the reporting likelihood when variants labeled as "maybe report" after ACMG-based classification were included. In three cases of population frequent but disease-associated variants, there was a difference in favor of reporting after ABC classification. A possible reason is that ABC step C (standard variant comments) allows a variant to be reported in one clinical setting but not another, e.g., based on Bayesian-based likelihood calculation of clinical relevance. Finally, the selection of ACMG criteria was compared between 36 laboratories. When excluding criteria used by less than four laboratories (<10%), the average concordance rate was 46%. Taken together, ABC-based classification is more clear-cut than ACMG-based classification since molecular and clinical information is handled separately, and variant reporting can be adapted to the clinical question and phenotype. Furthermore, variants do not get a clinically inappropriate label, like pathogenic when not pathogenic in a clinical context, or variant of unknown significance when the significance is known.