Gene-specific ACMG/AMP classification criteria for germline APC variants: Recommendations from the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Spier, Isabel, Yin, Xiaoyu, Richardson, Marcy, Pineda, Marta, Laner, Andreas, Ritter, Deborah, Boyle, Julie, Mur, Pilar, Hansen, Thomas v O., Shi, Xuemei, Mahmood, Khalid, Plazzer, John-Paul, Ognedal, Elisabet, Nordling, Margareta, Farrington, Susan M., Yamamoto, Gou, Baert-Desurmont, Stéphanie, Martins, Alexandra, Borras, Ester, Tops, Carli, Webb, Erica, Beshay, Victoria, Genuardi, Maurizio, Pesaran, Tina, Capellá, Gabriel, Tavtigian, Sean V., Latchford, Andrew, Frayling, Ian M., Plon, Sharon E., Greenblatt, Marc, Macrae, Finlay A. and Aretz, Stefan 2024. Gene-specific ACMG/AMP classification criteria for germline APC variants: Recommendations from the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel. Genetics in Medicine 26 (2) , 100992. 10.1016/j.gim.2023.100992

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Abstract

Purpose The Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) was established by the International Society for Gastrointestinal Hereditary Tumours and the Clinical Genome Resource, who set out to develop recommendations for the interpretation of germline APC variants underlying Familial Adenomatous Polyposis, the most frequent hereditary polyposis syndrome. Methods Through a rigorous process of database analysis, literature review, and expert elicitation, the APC VCEP derived gene-specific modifications to the ACMG/AMP (American College of Medical Genetics and Genomics and Association for Molecular Pathology) variant classification guidelines and validated such criteria through the pilot classification of 58 variants. Results The APC-specific criteria represented gene- and disease-informed specifications, including a quantitative approach to allele frequency thresholds, a stepwise decision tool for truncating variants, and semiquantitative evaluations of experimental and clinical data. Using the APC-specific criteria, 47% (27/58) of pilot variants were reclassified including 14 previous variants of uncertain significance (VUS). Conclusion The APC-specific ACMG/AMP criteria preserved the classification of well-characterized variants on ClinVar while substantially reducing the number of VUS by 56% (14/25). Moving forward, the APC VCEP will continue to interpret prioritized lists of VUS, the results of which will represent the most authoritative variant classification for widespread clinical use.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Elsevier
ISSN:	1098-3600
Date of First Compliant Deposit:	6 February 2024
Date of Acceptance:	27 September 2023
Last Modified:	09 Feb 2024 11:00
URI:	https://orca.cardiff.ac.uk/id/eprint/166142

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