Grant Number:	2U24CA258119-05A1 Interpret this number
Primary Investigator:	Greenblatt, Marc
Organization:	University Of Vermont & St Agric College
Project Title:	Insight Hereditary Colorectal Cancer Polyposis (IHCP)
Fiscal Year:	2026

PROJECT SUMMARY InSiGHT Hereditary Colon Cancer/ Polyposis (IHCP) Variant Curation Expert Panel (VCEP) The goal of the InSiGHT-ClinGen Polyposis /Colon Cancer (IHCP) Variant Curation Expert Panel (VCEP) is to maintain a multidisciplinary panel of Biocurators and Experts to curate the pathogenicity of genetic variants for multiple genes associated with Colon Polyposis and Hereditary Colorectal Cancer (CRC), which are common indications for genetic testing for cancer risk assessment. The International Society for Gastrointestinal Hereditary Tumors (InSIGHT) Variant Interpretation Committee (VIC), composed of dozens of world experts in all areas of variant curation (including the PIs and many of our Key Personnel), began classification work in 2011, but was limited to variants in the Mismatch Repair (MMR) genes that cause Lynch syndrome. In 2021, we formed the IHCP VCEP, an organized variant curation effort adding 7 non-MMR genes (APC, MUTYH, STK11, SMAD4, BMPR1A, POLD1, POLE) that are definitively linked to polyposis and CRC. The IHCP VCEP has continued the VIC’s leadership in establishing variant curation schemes for hereditary cancer. Our U24 award’s support for Experts, Coordinators, and Biocurators provided the “activation energy” to create an expanded team to curate variants in the 7 non-MMR hereditary polyposis/CRC genes. This proposal extends the efforts of the VCEP by addressing 3 new genes and integrating innovative methods to overcome barriers in variant classification. Our VCEP has made major progress in developing gene-specific rules for classifying variants in hereditary CRC genes. Despite this, most variants in CRC-polyposis genes in the ClinVar database hosted at the NCBI, one of the world’s main sources of variant data, are still classified as Variants of Uncertain Significance (VUS), even in the most well-studied non-MMR CRC genes. We have identified barriers to the goals of classifying variants and disseminating these classifications to the broader CRC genetics community. In the next iteration of our work, we will continue our curation work, extend it to newly identified genes, and systematically address barriers. Specific Aims are: 1. Continue classifying variants through our existing subVCEPs and create a new subVCEP to curate variants for RNF43, AXIN2, & NTHL1, genes newly designated as Definitively associated with Polyposis-CRC. 2. Update in silico data using calibrated algorithms for missense and splicing variant prediction. 3. Use large-scale data to select promising VUS that are near thresholds for Likely Pathogenic or Benign for systematic data mining (Clinical Phenotype, Literature). 4. Collaborate with ClinGen Variant Curation Interface (VCI) team, providing test cases of bulk data of genes from our VCEP as “use cases” to optimize the VCI for large scale variant curation and dissemination. Collectively, the VCEP team has the scientific, clinical, and administrative expertise to advance variant curation efforts for genes for hereditary CRC and polyposis, a common, important pre-cancerous condition.