TY - JOUR

T1 - Gene-specific ACMG/AMP classification criteria for germline APC variants

T2 - Recommendations from the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

AU - Spier, Isabel

AU - Yin, Xiaoyu

AU - Richardson, Marcy

AU - Pineda, Marta

AU - Laner, Andreas

AU - Ritter, Deborah

AU - Boyle, Julie

AU - Mur, Pilar

AU - Hansen, Thomas v.O.

AU - Shi, Xuemei

AU - Mahmood, Khalid

AU - Plazzer, John Paul

AU - Ognedal, Elisabet

AU - Nordling, Margareta

AU - Farrington, Susan M.

AU - Yamamoto, Gou

AU - Baert-Desurmont, Stéphanie

AU - Martins, Alexandra

AU - Borras, Ester

AU - Tops, Carli

AU - Webb, Erica

AU - Beshay, Victoria

AU - Genuardi, Maurizio

AU - Pesaran, Tina

AU - Capellá, Gabriel

AU - Tavtigian, Sean V.

AU - Latchford, Andrew

AU - Frayling, Ian M.

AU - Plon, Sharon E.

AU - Greenblatt, Marc

AU - Macrae, Finlay A.

AU - Aretz, Stefan

AU - InSiGHT-ClinGen Hereditary Colon Cancer/Polyposis Variant Curation Expert Panel

N1 - Funding Information: This work was supported (not financially) by the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS)- Project ID No 739547. ERN GENTURIS is partly co-funded by the European Union within the framework of the Third Health Programme “ERN-2016—Framework Partnership Agreement 2017-2021.” We also thank Mireia Menéndez for her support in interpretation of the functional assays. This publication was supported in part by the National Human Genome Research Institute of the National Institutes of Health for the Baylor College of Medicine/Stanford University Clinical Genome Resource-2U24HG009649 and from the National Cancer Institute U24 Curation Panels through the U24CA258119. It also was supported in part by the Intramural Research Program of the National Library of Medicine, National Institutes of Health, and the Spanish Ministry of Science and Innovation, co-funded by FEDER funds—a way to build Europe—(grant PID2019-111254RB-I00), CIBERONC (CB16/12/00234), and the Government of Catalonia (2017SGR1282). We thank CERCA Programme/Generalitat de Catalunya for institutional support. Finally, this research was supported in part by the Cancer Research UK Programme Award DRCPGM 100012. The content is solely the responsibility of the authors and does not necessarily represents the official views of the National Institutes of Health. These funding sources had no involvement in the study design; the collection, analysis, or interpretation of data; the writing of the report; or the decision to submit the manuscript for publication. The corresponding author had full access to all study data and had final responsibility for the decision to submit the manuscript for publication. Conceptualization: I.S. X.Y. M.G. S.A. F.A.M. S.E.P.; Data Curation: I.S. X.Y. M.R. M.P. A.Laner, J.B. P.M. T.v.O.H. X.S. K.M. E.B. C.T. E.W. V.B.; Formal Analysis: I.S. X.Y. M.R. M.P. A.Laner, J.B. P.M. T.v.O.H. X.S. K.M.; Funding Acquisition: M.G. F.A.M. S.A.; Investigation: I.S. X.Y. M.R. M.P.; Methodology: I.S. X.Y. M.R. D.R. S.E.P.; Project Administration: I.S. X.Y. D.R. J.-P.P.; Resources: E.B. C.T. E.W. V.B. G.Y. S.B.-D.; Software: M.G. S.V.T.; Supervision: I.S. M.P. M.G. T.P. G.C. S.V.T. A.Laner, A.Latchford, I.M.F. S.E.P. M.G. F.A.M. S.A.; Validation: I.S. X.Y. M.R. A.L. M.G. S.A.; Visualization: I.S. X.Y. S.A.; Writing-original draft: X.Y. I.S. S.A.; Writing-review and editing: I.S. S.A. M.R. A.Laner, T.v.H.O. J.-P.P. E.O. M.N. S.M.F. A.M. M.G. S.V.T. G.C. A.Latchford, I.M.F. S.E.P. M.G. F.A.M. I.S. and X.Y. contributed equally as the first authors. This study was conducted in accordance with the guidelines of the Ethics Committee of the Medical Faculty of the University of Bonn and the 1975 Declaration of Helsinki. Participants of clinical genetic testing gave written informed consent for their data to be used for clinical research and genetic investigations according to local regulations. Funding Information: This work was supported (not financially) by the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS)- Project ID No 739547. ERN GENTURIS is partly co-funded by the European Union within the framework of the Third Health Programme “ERN-2016—Framework Partnership Agreement 2017-2021.” We also thank Mireia Menéndez for her support in interpretation of the functional assays. Funding Information: This publication was supported in part by the National Human Genome Research Institute of the National Institutes of Health for the Baylor College of Medicine/Stanford University Clinical Genome Resource-2U24HG009649 and from the National Cancer Institute U24 Curation Panel s through the U24CA258119. It also was supported in part by the Intramural Research Program of the National Library of Medicine, National Institutes of Health, and the Spanish Ministry of Science and Innovation, co-funded by FEDER funds—a way to build Europe—(grant PID2019-111254RB-I00), CIBERONC (CB16/12/00234), and the Government of Catalonia (2017SGR1282). We thank CERCA Programme/Generalitat de Catalunya for institutional support. Finally, this research was supported in part by the Cancer Research UK Programme Award DRCPGM 100012. Publisher Copyright: © 2023 The Authors

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

KW - ACMG/AMP variant classification guidelines

KW - Adenomatous polyposis coli (APC)

KW - ClinGen

KW - Familial adenomatous polyposis (FAP)

KW - InSiGHT

U2 - 10.1016/j.gim.2023.100992

DO - 10.1016/j.gim.2023.100992

M3 - Journal article

C2 - 37800450

AN - SCOPUS:85179054274

VL - 26

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 2

M1 - 100992

ER -