Do Physicians Understand Uncertain Variants and Other Genetic Test Results?

描述(申请人提供)：BRCA1和BRCA2乳腺癌-卵巢癌易感基因的突变检测已经在70,000多人中进行。像其他基于序列的测试一样，结果可以揭示正常的序列、明显有害的突变或不确定意义的序列变体(VUS)，在这些情况下，VUS是否会增加癌症风险尚不清楚。VUS结果令人困惑，在大约12%的测试中会出现。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，还没有发表研究来评估非遗传学家医生接受BRCA基因测序的VUS结果的解释和临床建议，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，可能导致不适当的治疗建议。 假设：非遗传学家内科医生在建议乳腺癌和卵巢癌风险管理时，不会区分VUS和有害突变。研究设计：我们将优化和管理德克萨斯医学会成员(内科医生、家庭医生、产科妇科医生、普通外科医生和肿瘤学家)的在线问卷，其中包括有害的、阴性的或具有一个或多个VU的BRCA测试结果。癌症遗传学专家的控制组将包括在内。医生将被询问家庭中高危个体的测试选项，测试结果对癌症风险的影响，并要求他们在一系列管理选项中进行选择。统计分析将确定对VUS结果的反应路径是否更类似于明显有害的结果或负面结果。这些结果将被用来开发适当的符合CME标准的教育材料，并设计基因测试报告格式，以减少调查中发现的混乱领域。相关性：与NHGRI将“基因组学带到健康”的目标一致，我们必须优化各种医生专业对基于序列的基因测试的适当解释，以用于临床决策。随着对各种罕见和常见疾病的复杂检测模式的日益普及，例如DNA和RNA基因芯片，在开发这些检测的同时，必须有适当的报告和医生教育。

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.