Do Physicians Understand Uncertain Variants and Other Genetic Test Results?

描述（由申请人提供）：已在70，000多名个体中进行了BRCA 1和BRCA 2乳腺癌-卵巢癌易感基因突变检测。与其他基于序列的测试一样，结果可以显示正常序列，明显有害的突变或不确定意义的序列变体（VUS），其中不知道VUS是否会增加癌症风险。VUS结果令人困惑，大约12%的测试中会出现。对它们的充分解释需要对遗传学原理、所用的实验室方法和系谱分析有基本的了解。然而，尚未发表任何研究来评估接受BRCA基因测序VUS结果的非遗传学家医生的解释和临床建议，我们自己的临床经验表明，许多医生将所有VUS结果归类为有害突变，可能导致不适当的管理建议。 假设：非遗传学医生在对乳腺癌和卵巢癌风险管理提出建议时，不区分VUS和有害突变。研究设计：我们将优化并管理德克萨斯州医学协会的成员（内科医生，家庭医生，妇产科医生，普通外科医生和肿瘤学家）的在线问卷，该问卷提供了包括BRCA检测结果为有害，阴性或有一个或多个VUS的病例场景。将包括一个癌症遗传学专家对照组。医生将被询问家庭中有风险的个体的测试选项，测试结果对癌症风险的影响，并被要求在一系列管理选项中进行选择。统计分析将确定对VUS结果的反应的“路径”是否更类似于明显有害或阴性的结果。这些结果将用于开发适当的CME合格的教育材料，并设计基因检测报告格式，以减少调查中发现的混淆领域。相关性：与NHGRI的目标一致，将“基因组学用于健康”，我们必须优化各种医生专业用于临床决策的基于序列的基因检测的适当解释。随着复杂的检测模式，如DNA和RNA基因芯片，对各种罕见和常见疾病的日益可用性，适当的报告和医生教育必须伴随着这些测试的发展。

DESCRIPTION (provided by applicant): Testing for mutations in the BRCA1 and BRCA2 breast-ovarian cancer susceptibility genes has been performed in over 70,000 individuals. Like other sequence-based tests, the results can reveal a normal sequence, a clearly deleterious mutation or a sequence variant of uncertain significance (VUS), in which it is not known whether the VUS confers an increased cancer risk. VUS results are confusing and occur in approximately 12% of tests. Their adequate interpretation requires a basic understanding of genetic principles, the laboratory methods utilized and pedigree analysis. No studies, however, have been published that assess the interpretation and clinical recommendations of non-geneticist physicians receiving a VUS result for BRCA gene sequencing and our own clinical experience suggests that many physicians categorize all VUS results as deleterious mutations potentially leading to inappropriate management recommendations. Hypothesis: Non-geneticist physicians do not discriminate between a VUS and a deleterious mutation when making recommendations with regard to breast and ovarian cancer risk management. Study Design: We will optimize and administer to members of the Texas Medical Association (internists, family practitioners, obstetrician-gynecologists, general surgeons, and oncologists) an on-line questionnaire that presents case scenarios that include BRCA test results that are deleterious, negative or have one or more VUS. A control group of experts in cancer genetics will be included. Physicians will be queried on testing options for at-risk individuals in the family, impact of the test result on cancer risk and asked to choose among a range of management options. Statistical analysis will determine whether the "path" of responses to a VUS result is more similar to a clearly deleterious or negative result. These results will be used to develop appropriate CME-eligible educational materials and to design genetic testing report formats that decrease areas of confusion identified in the survey. Relevance: Consistent with the goals of the NHGRI to bring "Genomics to Health" it is imperative that we optimize the appropriate interpretation of sequence-based genetic tests by a variety of physician specialties for use in clinical decision making. With the increasing availability of complex testing modalities, e.g. DNA and RNA gene chips, for a variety of both rare and common diseases, appropriate reporting and physician education must accompany the development of these tests.