Gene-Specific Acmg/Amp Classification Criteria for Germline Apc Variants: Recommendations From the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel\

Authors

Isabel Spier
Xiaoyu Yin
Marcy Richardson
Marta Pineda
Andreas Laner
Deborah Ritter
Julie Boyle
Pilar Mur
Thomas V O Hansen
Xuemei Shi
Khalid Mahmood
John-Paul Plazzer
Elisabet Ognedal
Margareta Nordling
Susan M Farrington
Gou Yamamoto
Stéphanie Baert-Desurmont
Alexandra Martins
Ester Borras
Carli Tops
Erica Webb
Victoria Beshay
Maurizio Genuardi
Tina Pesaran
Gabriel Capellá
Sean V Tavtigian
Andrew Latchford
Ian M Frayling
Sharon E Plon
Marc Greenblatt
Finlay A Macrae
Stefan Aretz
InSiGHT-ClinGen Hereditary Colon Cancer/Polyposis Variant Curation Expert Panel

Publication Date

2-1-2024

Journal

Genetics in Medicine

DOI

10.1016/j.gim.2023.100992

PMID

37800450

PMCID

PMC10922469

PubMedCentral® Posted Date

2-1-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Genetic Testing, Genetic Variation, Adenomatous Polyposis Coli, Germ-Line Mutation, Germ Cells, ACMG/AMP variant classification guidelines, APC, ClinGen, InSiGHT, Familial adenomatous polyposis, variant interpretation

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.