Expert curation of germline APC sequence variants through further development of the InSiGHT LOVD and specification of the ACMG/AMP classification guidelines

Xiaoyu Sherry Yin1,2, Isabel Spier3,4, Johan T. den Dunnen5, Finlay A. Macrae1,6, Stefan Aretz3,4

1Department of Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, Australia. 2Melbourne Medical School, University of Melbourne, Parkville, Australia. 3Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany. 4Institute of Human Genetics, University of Bonn, Bonn, Germany. 5Department of Human Genetics and Clinical Genetics, Leiden University, Leiden, Netherlands. 6Department of Medicine, University of Melbourne, Parkville, Australia


Objectives: This study aims to improve data centralisation and standardisation across existing databases for the APC gene. The overall objective is to develop a set of gene-specific criteria for the expert curation of APC variants.

Methods: A novel reference APC database was established and hosted on the Leiden Open Variation Database ( Incongruent variant interpretation within this centralised database was scrutinised, as well as those in the ClinVar database. In developing APC-specific assertion criteria, adaptations of the generic classification framework published by the American College of Medical Genetics and the Association of Molecular Pathology (ACMG/AMP) were made based on expert opinions (1).

Results: 49% of the 168 variants with conflicting interpretation in the ClinVar database was classified as benign based on the modified stand-alone BA1 criterion. The InSiGHT LOVD contained 31 variants of conflicting interpretation, 10% were reclassified as benign based on BA1. A comprehensive literature review identified functional analysis of 11 of the remaining variants and 43 additional non-canonical splicing variants. Classification of these variants based on the APC-specific ACMG/AMP criteria was attempted, which awaits further validation by the InSiGHT APC Variant Curation Expert Panel (VCEP).

Conclusions: An InSiGHT VCEP was constituted in collaboration with ClinGen, who will refine and justify the modified criteria by pilot testing a group of known pathogenic, benign variants and variants with uncertain significance. A list of prioritised variants will then be classified by the VCEP at 3 monthly interval, whose consensus will represent the most authoritative classification of pathogenicity for widespread clinical use.

Abstract references

  1. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-23.