InSiGHT-ClinGen Polyposis/Colon Cancer Variant Curation Expert Panel

摘要：InSIGHT-ClinGen息肉病/结肠癌（ICPC）变异治愈专家小组（VCEP） InSiGHT-ClinGen息肉病/结肠癌（ICPC）变异治愈专家小组（VCEP）的目标是 建立并维持一个由生物学家和专家组成的多学科小组，以管理遗传病的致病性。 与结肠息肉病和遗传性结直肠癌（CRC）相关的基因的变体。美国国立卫生研究院已经 优先鉴定与高优先级疾病相关的基因组变异， 对诊断和治疗的临床意义。临床基因组（ClinGen）项目，NIH资助 自2013年以来，致力于定义用于精准医学的基因和变体的临床相关性 与研究我们的ICPC VCEP解决了一个主要的临床需求，即管理多个基因， 息肉病和遗传性CRC，这是癌症风险评估基因检测的常见指征。 VCEP代表了两项主要工作的合并：1）国际遗传变异分类 胃肠道遗传性肿瘤学会（InSIGHT），由InSIGHT变体进行 自2011年以来，解释委员会（维克），但仅限于错配修复（MMR）的变体 导致林奇综合症的基因2)ClinGen结肠癌基因治疗专家小组（CRC GCEP）， 一个没有资金的工作组（WG）。CRC GCEP由本提案的联合PI共同主持， 基因-表型关联（Seifert 2019），但尚未策划个体变异。此外，ClinGen 序列变异解释（SVI）工作组一直在完善由 美国医学遗传学和基因组学学院（ACMG）和分子病理学协会。 这些团队的成员（InSIGHT维克和ClinGen CRC GCEP，以及ClinGen SVI的输入）已准备就绪 将变异治疗工作扩展到新的结肠癌和息肉病风险基因。我们的ICPC VCEP计划提供 为多个基因的可持续管理活动建立必要的行政结构。具体 目的是：1）创建和维护一个由生物学家、协调员和专家组成的VCEP，以管理致病性 与结肠息肉病和遗传性CRC相关的基因的遗传变异; 2）分析和分类 来自：APC、MUTYH、STK 11、SMAD 4、BMPR 1A、POLE和POLD 1基因的变体; 3）执行基因-表型 对一些有报道证据表明与息肉病或结直肠癌相关的基因进行治疗，但尚未 被发现是强制性的或强的，以指导未来的VCEP工作。我们将利用程序、接口、工具 和来自ClinGen和NCBI ClinVar数据库的信息学基础设施。总的来说，VCEP PI和 Co-Is拥有科学，临床和管理专业知识，以推进变体策展工作， 常见的、重要的癌前临床状况、遗传性息肉病和CRC。

ABSTRACT: InSiGHT-ClinGen Polyposis /Colon Cancer (ICPC) Variant Curation Expert Panel (VCEP) The goal of the InSiGHT-ClinGen Polyposis /Colon Cancer (ICPC) Variant Curation Expert Panel (VCEP) is to create and maintain a multidisciplinary panel of Biocurators and Experts to curate the pathogenicity of genetic variants for genes associated with Colon Polyposis and Hereditary Colorectal Cancer (CRC). The NIH has prioritized identifying genomic variants associated with diseases of high priority and systematically determining their clinical significance for diagnosis and treatment. The Clinical Genome (ClinGen) project, NIH-funded since 2013, is dedicated to defining the clinical relevance of genes and variants for use in precision medicine and research. Our ICPC VCEP addresses a major clinical need, that of curating multiple genes that predispose to polyposis and hereditary CRC, which are common indications for genetic testing for cancer risk assessment. The VCEP represents a merger of two major efforts: 1) Classification of genetic variants by the International Society for Gastrointestinal Hereditary Tumors (InSIGHT), which has been ongoing by the InSIGHT Variant Interpretation Committee (VIC) since 2011, but has been limited to variants in the Mismatch Repair (MMR) genes that cause Lynch syndrome. 2) The ClinGen Colon Cancer Gene Curation Expert Panel (CRC GCEP), an unfunded working group (WG). The CRC GCEP, Co-chaired by the Co-PIs of this proposal, has evaluated gene-phenotype associations (Seifert 2019) but has not curated individual variants. Also, the ClinGen Sequence Variant Interpretation (SVI) working group has been refining variant curation rules established by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology. Members of these teams (InSiGHT VIC and ClinGen CRC GCEP, with input from the ClinGen SVI) are primed to expand variant curation efforts to new colon cancer and polyposis risk genes. Our ICPC VCEP plan provides the necessary administrative structure for sustainable ongoing curation activities for multiple genes. Specific Aims are: 1) Create and maintain a VCEP of Biocurators, Coordinator, and Experts to curate the pathogenicity of genetic variants for genes associated with Colon Polyposis and Hereditary CRC; 2) Analyze and classify variants from: APC, MUTYH, STK11, SMAD4, BMPR1A, POLE, & POLD1 genes; 3) Perform gene-phenotype curation on genes with some reported evidence of association with polyposis or colorectal cancer, but not yet found to be Definitive or Strong, to guide future VCEP efforts. We will utilize the procedures, interfaces, tools and informatics infrastructure from ClinGen and the NCBI ClinVar database. Collectively, the VCEPs PIs and Co-Is have the scientific, clinical, and administrative expertise to advance variant curation efforts for a common, important pre-cancerous clinical condition, hereditary polyposis and CRC.