BRCA1/2 and Hereditary Breast, Ovarian and Pancreatic (HBOP) Cancer Variant Curation Expert Panels

项目摘要 在乳腺癌、卵巢癌和胰腺癌易感基因中存在生殖系变异的女性， 在他们的一生中患上这些癌症的风险增加。临床遗传性癌症基因检测 这些基因中的致病性变体已经成为临床实践的重要部分。大部分的好处 基因检测与BRCA 1和BRCA 2基因相关，因为风险管理，手术 预防和靶向治疗的好处与知识的存在癌症易感 致病变异体。然而，在包括ATM在内的其他易感基因中鉴定致病性变异， BARD 1、BRIP 1、CHEK 2、PALB 2、RAD 51 C和RAD 51 D也具有临床意义，因为携带者可能 有资格接受乳腺癌、卵巢癌和胰腺癌的强化筛查。然而，这一过程往往 由于无法确定这些基因中变异的临床相关性而变得复杂。缺少资料 对这些变异的了解意味着携带生殖系变异的个体通常不能从增加的风险中获益 评估和管理，或就手术预防或定制治疗做出明智的决定 选项.为了解决这一问题，我们开发了ClinGen BRCA 1/2变异体治疗专家组（VCEP） 和遗传性乳腺、卵巢和胰腺（HBOP）VCEP。我们将开发类似ACMG的基于规则的 本文描述了用于上述每个基因中的变体分类的方法，并将这些规则应用于 观察到这些基因的变异。因此，本申请的目的是对临床 通过BRCA 1/2 VCEP和ATM中的变体，BRCA 1和BRCA 2中的种系变体的相关性， BARD 1、BRIP 1、CHEK 2、PALB 2、RAD 51 C和RAD 51 D通过HBOP VCEP。的结果 建议的管理工作将输入ClinGen变体管理界面，并提供给 通过ClinVar和BRCA Exchange网站公开。

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.