Grant Number:	2U24CA258058-04 Interpret this number
Primary Investigator:	Couch, Fergus
Organization:	Mayo Clinic Rochester
Project Title:	Curation Expert Panels for BRCA1/2 and Hereditary Breast, Ovarian and Pancreatic (HBOP) Cancer Genes
Fiscal Year:	2025

PROJECT SUMMARY Individuals with germline variants in breast, ovarian and pancreatic cancer predisposition genes are at significantly elevated risk of developing these cancers in their lifetime. Clinical hereditary cancer genetic testing for pathogenic variants in these genes has become an important part of clinical practice. Much of the benefits of genetic testing are associated with the BRCA1 and BRCA2 genes because of the risk management, surgical prevention and targeted treatment benefits associated with knowledge of the presence of a cancer predisposing pathogenic variants. However, identification of pathogenic variants in other predisposition genes including ATM, BARD1, BRIP1, CHEK2, PALB2, RAD51C and RAD51D is also clincially meaningful because carriers may qualify for enhanced screening for breast, ovarian and pancreatic cancer. However, this process is often complicated by an inability to establish the clinical relevance of variants in these genes. This lack of information about these variants means that individuals carrying germline variants often cannot benefit from enhanced risk assessment and management or make informed decisions about surgical prevention or tailored treatment options. To address this issue, we developed the BRCA1/2 and Hereditary Breast, Ovarian, and Pancreatic (HBOP) Variant Curation Expert Panels (VCEPs). We will build upon our initial work to implement ClinGen rules- based methods for variant classification in BRCA1, BRCA2, ATM and PALB2 and also develop and implement rules for curation of variants in CHEK2, RAD51C, RAD51D, BARD1 and BRIP1. Thus, the goal of this application is to curate and classify the clinical relevance of germline variants in BRCA1 and BRCA2 through a BRCA1/2 VCEP and variants in ATM, BARD1, BRIP1, CHEK2, PALB2, RAD51C and RAD51D through the HBOP VCEP. The results from the proposed curation efforts will be entered into the ClinGen Variant Curation Interface and made available to the public through the ClinVar and BRCA Exchange websites.




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Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline PALB2 sequence variants.
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Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.
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Integration of protein stability and AlphaMissense scores improves bioinformatic impact prediction for p53 missense and in-frame amino acid deletion variants.
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Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset.
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Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.
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Atypical cancer risk profile in carriers of Italian founder BRCA1 variant p.His1673del: Implications for classification and clinical management.
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Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline ATM sequence variants.
Authors: Richardson M.E. , Holdren M. , Brannan T. , de la Hoya M. , Spurdle A.B. , Tavtigian S.V. , Young C.C. , Zec L. , Hiraki S. , Anderson M.J. , et al. .
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