Large-scale application of ClinGen-InSiGHT APC-specific ACMG/AMP variant classification criteria leads to substantial reduction in VUS

Xiaoyu Yin; Marcy Richardson; Andreas Laner; Xuemei Shi; Elisabet Ognedal; Valeria Vasta; Thomas V O Hansen; Marta Pineda; Deborah Ritter; Johan de Dunnen; Emadeldin Hassanin; Wencong Lyman Lin; Ester Borras; Karl Krahn; Margareta Nordling; Alexandra Martins; Khalid Mahmood; Emily Nadeau; Victoria Beshay; Carli Tops; Maurizio Genuardi; Tina Pesaran; Ian M Frayling; Gabriel Capellá; Andrew Latchford; Sean V Tavtigian; Carlo Maj; Sharon E Plon; Marc S Greenblatt; Finlay A Macrae; Isabel Spier; Stefan Aretz

doi:10.1016/j.ajhg.2024.09.002

Large-scale application of ClinGen-InSiGHT APC-specific ACMG/AMP variant classification criteria leads to substantial reduction in VUS

Am J Hum Genet. 2024 Nov 7;111(11):2427-2443. doi: 10.1016/j.ajhg.2024.09.002. Epub 2024 Oct 1.

Authors

Xiaoyu Yin¹, Marcy Richardson², Andreas Laner³, Xuemei Shi⁴, Elisabet Ognedal⁵, Valeria Vasta⁶, Thomas V O Hansen⁷, Marta Pineda⁸, Deborah Ritter⁹, Johan de Dunnen¹⁰, Emadeldin Hassanin¹¹, Wencong Lyman Lin¹², Ester Borras¹³, Karl Krahn¹⁴, Margareta Nordling¹⁵, Alexandra Martins¹⁶, Khalid Mahmood¹⁷, Emily Nadeau¹⁸, Victoria Beshay¹⁹, Carli Tops¹⁰, Maurizio Genuardi²⁰, Tina Pesaran², Ian M Frayling²¹, Gabriel Capellá⁸, Andrew Latchford²², Sean V Tavtigian²³, Carlo Maj²⁴, Sharon E Plon⁹, Marc S Greenblatt¹⁸, Finlay A Macrae²⁵, Isabel Spier²⁶, Stefan Aretz²⁷

Affiliations

¹ Department of Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, VIC, Australia; Department of Medicine, University of Melbourne, Parkville, VIC, Australia; Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.
² Ambry Genetics, Aliso Viejo, CA, USA.
³ Medical Genetics Center Munich, MGZ Munich, Germany.
⁴ Greenwood Genetic Center, Greenwood, SC, USA.
⁵ Western Norway Familial Cancer Center, Haukeland University Hospital, Bergen, Norway.
⁶ Northwest Genomics Center, Department of Genome Sciences, University of Washington, Seattle, WA, USA.
⁷ Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸ European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, the Netherlands; Hereditary Cancer Program, Catalan Institute of Oncology - ONCOBELL, IDIBELL, Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, Madrid, Spain.
⁹ Baylor College of Medicine, Houston, TX, USA; Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX, USA.
¹⁰ Departments of Human Genetics & Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
¹¹ Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Bonn, Germany; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
¹² St Vincents Hospital Melbourne, East Melbourne, VIC, Australia.
¹³ Invitae Corporation, San Francisco, CA, USA.
¹⁴ GeneDx, Gaithersburg, MD, USA.
¹⁵ Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Clinical Genetics, Linköping University Hospital, Linköping, Sweden.
¹⁶ Université de Rouen Normandie, Inserm U1245, 76000 Rouen, France.
¹⁷ Colorectal Oncogenomics Group, Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.
¹⁸ Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
¹⁹ Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
²⁰ Fondazione Policlinico Universitario A. Gemelli IRCCS, and Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy.
²¹ Polyposis Registry, St Mark's Hospital, London, UK; Inherited Tumour Syndromes Research Group, Institute of Cancer & Genetics, Cardiff University, Cardiff, UK; National Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland.
²² Polyposis Registry, St Mark's Hospital, London, UK; Department of Surgery and Cancer, Imperial College, London, UK.
²³ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Department of Oncological Sciences, School of Medicine, University of Utah, Salt Lake City, UT, USA.
²⁴ Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Bonn, Germany; Centre for Human Genetics, University of Marburg, Marburg, Germany.
²⁵ Department of Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, VIC, Australia; Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
²⁶ Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany; European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, the Netherlands; National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.
²⁷ Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany; European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, the Netherlands; National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany. Electronic address: [email protected].

Abstract

Pathogenic constitutional APC variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUSs), APC-specific variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) based on the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). A streamlined algorithm using the APC-specific criteria was developed and applied to assess all APC variants in ClinVar and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) international reference APC Leiden Open Variation Database (LOVD) variant database, which included a total of 10,228 unique APC variants. Among the ClinVar and LOVD variants with an initial classification of (likely) benign or (likely) pathogenic, 94% and 96% remained in their original categories, respectively. In contrast, 41% ClinVar and 61% LOVD VUSs were reclassified into clinically meaningful classes, the vast majority as (likely) benign. The total number of VUSs was reduced by 37%. In 24 out of 37 (65%) promising APC variants that remained VUS despite evidence for pathogenicity, a data-mining-driven work-up allowed their reclassification as (likely) pathogenic. These results demonstrated that the application of APC-specific criteria substantially reduced the number of VUSs in ClinVar and LOVD. The study also demonstrated the feasibility of a systematic approach to variant classification in large datasets, which might serve as a generalizable model for other gene- or disease-specific variant interpretation initiatives. It also allowed for the prioritization of VUSs that will benefit from in-depth evidence collection. This subset of APC variants was approved by the VCEP and made publicly available through ClinVar and LOVD for widespread clinical use.

Keywords: ACMG/AMP variant classification guidelines; APC; Adenomatous polyposis coli; ClinGen; FAP; InSiGHT; familial adenomatous polyposis.

MeSH terms

Adenomatous Polyposis Coli Protein* / genetics
Adenomatous Polyposis Coli* / genetics
Algorithms
Databases, Genetic*
Genetic Variation*
Genomics / methods
Humans

Substances

Adenomatous Polyposis Coli Protein
APC protein, human