||5U24CA258119-03 Interpret this number
||University Of Vermont & St Agric College
||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.
Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria.
, Byrne A.B.
, Feng B.J.
, Pagel K.A.
, Mooney S.D.
, Karchin R.
, O'Donnell-Luria A.
, Harrison S.M.
, Tavtigian S.V.
, Greenblatt M.S.
, et al.
American journal of human genetics, 2022-12-01; 109(12), p. 2163-2177.