Grant Number:	5U24CA258058-03 Interpret this number
Primary Investigator:	Couch, Fergus
Organization:	Mayo Clinic Rochester
Project Title:	BRCA1/2 and Hereditary Breast, Ovarian and Pancreatic (HBOP) Cancer Variant Curation Expert Panels
Fiscal Year:	2024

PROJECT SUMMARY Women 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 have developed a ClinGen BRCA1/2 Variant Curation Expert Panel (VCEP) and a Hereditary Breast, Ovarian, and Pancreatic (HBOP) VCEP. We will develop ACMG-like rules-based methods for variant classification in each of the genes described above and apply these rules to classification of observed variants in these genes. Thus, the Aim 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.




Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.
Authors: Parsons M.T. , de la Hoya M. , Richardson M.E. , Tudini E. , Anderson M. , Berkofsky-Fessler W. , Caputo S.M. , Chan R.C. , Cline M.S. , Feng B.J. , et al. .
Source: American Journal Of Human Genetics, 2024-09-05 00:00:00.0; 111(9), p. 2044-2058.
EPub date: 2024-08-13 00:00:00.0.
PMID: 39142283
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Atypical cancer risk profile in carriers of Italian founder BRCA1 variant p.His1673del: Implications for classification and clinical management.
Authors: Innella G. , Fortuno C. , Caleca L. , Feng B.J. , Carroll C. , Parsons M.T. , Miccoli S. , Montagna M. , Calistri D. , Cortesi L. , et al. .
Source: Cancer Medicine, 2024 Aug; 13(16), p. e70114.
PMID: 39194334
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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. .
Source: Medrxiv : The Preprint Server For Health Sciences, 2024-05-29 00:00:00.0; , .
EPub date: 2024-05-29 00:00:00.0.
PMID: 38854136
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