InSiGHT-ClinGen Polyposis/Colon Cancer Variant Curation Expert Panel

ABSTRACT: InSiGHT-ClinGen Polyposis /Colon Cancer (ICPC) Variant Curation Expert Panel (VCEP) The goal of the InSiGHT-ClinGen Polyposis /Colon Cancer (ICPC) Variant Curation Expert Panel (VCEP) is to create and maintain a multidisciplinary panel of Biocurators and Experts to curate the pathogenicity of genetic

variants for genes associated with Colon Polyposis and Hereditary Colorectal Cancer (CRC). The NIH has prioritized identifying genomic variants associated with diseases of high priority and systematically determining their clinical significance for diagnosis and treatment. The Clinical Genome (ClinGen) project, NIH-funded

since 2013, is dedicated to defining the clinical relevance of genes and variants for use in precision medicine and research. Our ICPC VCEP addresses a major clinical need, that of curating multiple genes that predispose to polyposis and hereditary CRC, which are common indications for genetic testing for cancer risk assessment.

The VCEP represents a merger of two major efforts: 1) Classification of genetic variants by the International Society for Gastrointestinal Hereditary Tumors (InSIGHT), which has been ongoing by the InSIGHT Variant Interpretation Committee (VIC) since 2011, but has been limited to variants in the Mismatch Repair (MMR)

genes that cause Lynch syndrome. 2) The ClinGen Colon Cancer Gene Curation Expert Panel (CRC GCEP), an unfunded working group (WG). The CRC GCEP, Co-chaired by the Co-PIs of this proposal, has evaluated gene-phenotype associations (Seifert 2019) but has not curated individual variants. Also, the ClinGen

Sequence Variant Interpretation (SVI) working group has been refining variant curation rules established by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology. Members of these teams (InSiGHT VIC and ClinGen CRC GCEP, with input from the ClinGen SVI) are primed

to expand variant curation efforts to new colon cancer and polyposis risk genes. Our ICPC VCEP plan provides the necessary administrative structure for sustainable ongoing curation activities for multiple genes. Specific Aims are: 1) Create and maintain a VCEP of Biocurators, Coordinator, and Experts to curate the pathogenicity

of genetic variants for genes associated with Colon Polyposis and Hereditary CRC; 2) Analyze and classify variants from: APC, MUTYH, STK11, SMAD4, BMPR1A, POLE, & POLD1 genes; 3) Perform gene-phenotype curation on genes with some reported evidence of association with polyposis or colorectal cancer, but not yet

found to be Definitive or Strong, to guide future VCEP efforts. We will utilize the procedures, interfaces, tools and informatics infrastructure from ClinGen and the NCBI ClinVar database. Collectively, the VCEPs PIs and Co-Is have the scientific, clinical, and administrative expertise to advance variant curation efforts for a

common, important pre-cancerous clinical condition, hereditary polyposis and CRC.