InSiGHT-ClinGen Polyposis/Colon Cancer Variant Curation Expert Panel

InSiGHT-ClinGen 息肉病/结肠癌变异治疗专家组

• 批准号: 10426086
• 负责人: MARC S GREENBLATT
• 金额: $ 26.82万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-10 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426086
• 关键词: APC gene; Accounting; Address; Age of Onset; American; Area; BMPR1A gene; Benign; Bioinformatics; Biological Assay; Classification; ClinVar; Clinical; Clinical Pathology; Colon; Colon Carcinoma; Colorectal Cancer; Communities; Custom; DNA; DNA Databases; Databases; Development; Diagnosis; Discipline; Disease; Familial colorectal cancer; Family; Funding; Future; Genes; Genetic; Genetic Diseases; Genetic testing for cancer risk; Genome; Genomics; Germ Lines; Goals; Hereditary Malignant Neoplasm; Hereditary Nonpolyposis Colorectal Neoplasms; Human Resources; Individual; Inherited; International; Link; MADH4 gene; Malignant neoplasm of gastrointestinal tract; Medical Genetics; Mismatch Repair; Oncogenes; Participant; Pathogenicity; Patients; Phenotype; Precancerous Polyp; Procedures; Recording of previous events; Reporting; Research; Research Personnel; Resources; Risk Assessment; STK11 gene; Scientist; Societies; Structure; Susceptibility Gene; Syndrome; System; Testing; Time; Training; United States National Institutes of Health; Variant; clinical infrastructure; clinically relevant; clinically significant; colorectal cancer risk; gastrointestinal; gene panel; gene repair; genetic counselor; genetic panel test; genetic testing; genetic variant; in silico; informatics infrastructure; insight; international scientific organization; medical schools; member; molecular diagnostics; molecular pathology; multidisciplinary; polyposis; precision medicine; premalignant; risk variant; tool; tumor; variant of unknown significance; working group

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.

摘要：洞察-克林根息肉/结肠癌(ICPC)变异治疗专家小组(VCEP) Insight-Clingen息肉/结肠癌(ICPC)变异治疗专家小组(VCEP)的目标是 创建和维护一个由生物治疗师和专家组成的多学科小组，以管理基因的致病性 与结肠息肉病和遗传性结直肠癌(CRC)相关的基因变异。美国国家卫生研究院已经 优先确定与高优先级疾病相关的基因组变异，并系统地确定 它们对诊断和治疗的临床意义。美国国立卫生研究院资助的临床基因组(Clingen)项目 自2013年以来，致力于定义用于精确医学的基因和变异的临床相关性 和研究。我们的ICPC VCEP解决了一个主要的临床需求，即管理多个易感基因 对于息肉病和遗传性CRC，这是癌症风险评估基因测试的常见适应症。 VCEP代表了两项主要工作的结合：1)国际遗传变异分类 胃肠道遗传性肿瘤学会(洞察力)，由洞察力变种进行 自2011年以来一直是解释委员会(VIC)，但一直限于错配修复(MMR)中的变体 导致林奇综合症的基因。2)克莱根结肠癌基因治疗专家组(CRC GCEP)， 一个没有资金的工作组(WG)。由这项提案的共同绩效指标共同担任主席的儿童权利公约政府执行委员会已经评估了 基因-表型关联(Seifert 2019)，但尚未对单个变种进行管理。还有，克莱根 序列变体解释(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(Insight VIC和Clingen CRC GCEP，来自Clingen SVI的投入)的成员都已做好准备 将变异筛选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 针对多种基因的可持续持续管理活动的必要行政结构。特定的 目标是：1)创建和维护由生物促进员、协调员和专家组成的VCEP，以管理病原性 大肠息肉和遗传性结直肠癌相关基因的遗传变异；2)分析和分类 APC、MUTYH、STK11、Smad4、BMPR1A、POLE和POLD1基因的变异体；3)表现基因表型 对一些与息肉病或结直肠癌有关的基因进行筛选，但目前还没有 被发现是决定性的或强有力的，以指导未来的VCEP努力。我们将利用程序、接口、工具 以及来自Clingen和NCBI ClinVar数据库的信息基础设施。总体而言，VCEP PI和 CO-IS拥有科学、临床和管理方面的专业知识，可推进针对 常见、重要的癌前临床症状、遗传性息肉病和结直肠癌。