biostudies-literatureYin XStanford UniversityNational Cancer Institute Division of Cancer Epidemiology and GeneticsU.S. National Library of MedicineNational Cancer InstituteBaylor College of MedicineNCI NIH HHSNational Institutes of HealthEuropean CommissionNational Human Genome Research Institute2427-2443https://www.ebi.ac.uk/biostudies/studies/S-EPMC11568752biostudies-literatureUnknown111(11)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 American journal of human geneticsLarge-scale application of ClinGen-InSiGHT APC-specific ACMG/AMP variant classification criteria leads to substantial reduction in VUS.PMC11568752U24CA2581192U24HG009649R01 CA264971739547Martins AVasta VPineda MCapella GOgnedal EMacrae FAShi XLin WLFrayling IMHansen TVONadeau ETavtigian SVBorras ESpier ILaner Ade Dunnen JPlon SEHassanin EYin XBeshay VRichardson MTops CKrahn KMahmood KAretz SPesaran TGreenblatt MSMaj CLatchford ARitter DGenuardi MNordling MfalseLarge-scale application of ClinGen-InSiGHT APC-specific ACMG/AMP variant classification criteria leads to substantial reduction in VUS.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 2024-01-01T00:00:00Z2024 Nov2026-06-03T05:38:39.685Z2025-04-03T23:56:28.597ZS-EPMC115687523935751710.1016/j.ajhg.2024.09.002