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

项目总结 具有乳腺癌、卵巢癌和胰腺癌易感基因胚系变异的女性显著 在他们一生中罹患这些癌症的风险增加。临床遗传性癌症基因检测 这些基因的致病变异已成为临床实践的重要组成部分。的大部分好处 基因检测与BRCA1和BRCA2基因相关，因为风险管理，外科手术 预防和靶向治疗受益于对癌症易感因素的了解 致病变种。然而，其他易感基因致病变异的鉴定包括ATM， BARD1、BRIP1、CHEK2、PALB2、RAD51C和RAD51D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，这一过程通常是 复杂的是无法确定这些基因中的变异的临床相关性。这种信息的缺乏 关于这些变异意味着携带生殖系变异的个体通常不能从风险增加中受益 评估和管理，或就手术预防或量身定做的治疗做出明智的决定 选择。为了解决这个问题，我们开发了一个Clingen BRCA1/2变体配置专家小组(VCEP) 和遗传性乳房、卵巢和胰腺(HBOP)VCEP。我们将开发类似ACMG的基于规则的 上述每个基因的变异分类方法，并将这些规则应用于 观察到了这些基因的变异。因此，该应用程序的目的是管理和分类临床 BRCA1和BRCA2中通过BRCA1/2 VCEP的生殖系变异与ATM中的变异的相关性， BARD1、BRIP1、CHEK2、PALB2、RAD51C和RAD51D通过HBOP VCEP。结果来自于 拟议的管理工作将进入Clingen变体管理界面，并提供给 通过ClinVar和BRCA交易所网站公开。

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.