A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes
A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes
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DOI：
10.1086/521032
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发表时间：
2007-11-01
影响因子：
9.8
通讯作者：
Goldgar, David E.
中科院分区：
文献类型：
--
作者：
Easton, Douglas F.;Deffenbaugh, Amie M.;Goldgar, David E.
乳腺癌和卵巢癌易感基因BRCA1和BRCA2的突变筛查正成为临床实践中越来越重要的部分。对这些基因中罕见的非截断序列变体进行分类是有问题的，因为尚不清楚这些细微的变化是否会充分改变功能，使细胞易于发生癌症。使用Myriad Genetic实验室数据库中近70,000个全序列测试的数据，我们评估了BRCA基因中1,433个未知意义的序列变体(VUS)的临床意义。在评估中采用了三个独立的衡量标准：具有已知有害突变的VU在反式中的共同出现；通过Logistic回归详细分析VU携带者先证者的个人和家族癌症病史；以及，在先证者的子集中，分析家系中的共同隔离与疾病。对于这些因素中的每一个，在假设VUS相当于相对于风险的中性有害突变的情况下，计算似然比。从每个成分得出的似然比被组合起来，以提供对每个VU的总体评估。共有133名VUS的赔率至少为100：1，支持风险中性，而43名VUS的赔率至少为20：1，支持有害。有证据支持因果关系的VUS是那些被预测影响剪接的VUS，落在BRCA同源基因中高度保守的位置，并且更有可能位于蛋白质的特定结构域。除了它们对改善患者及其家属的遗传学咨询的效用外，这里报告的全球评估对于功能分析、结构模型和计算机分析的验证将是非常宝贵的。
Mutation screening of the breast and ovarian cancer - predisposition genes BRCA1 and BRCA2 is becoming an increasingly important part of clinical practice. Classification of rare nontruncating sequence variants in these genes is problematic, because it is not known whether these subtle changes alter function sufficiently to predispose cells to cancer development. Using data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests, we assessed the clinical significance of 1,433 sequence variants of unknown significance ( VUSs) in the BRCA genes. Three independent measures were employed in the assessment: co-occurrence in trans of a VUS with known deleterious mutations; detailed analysis, by logistic regression, of personal and family history of cancer in VUS-carrying probands; and, in a subset of probands, an analysis of cosegregation with disease in pedigrees. For each of these factors, a likelihood ratio was computed under the hypothesis that the VUSs were equivalent to an "average" deleterious mutation, compared with neutral, with respect to risk. The likelihood ratios derived from each component were combined to provide an overall assessment for each VUS. A total of 133 VUSs had odds of at least 100: 1 in favor of neutrality with respect to risk, whereas 43 had odds of at least 20: 1 in favor of being deleterious. VUSs with evidence in favor of causality were those that were predicted to affect splicing, fell at positions that are highly conserved among BRCA orthologs, and were more likely to be located in specific domains of the proteins. In addition to their utility for improved genetics counseling of patients and their families, the global assessment reported here will be invaluable for validation of functional assays, structural models, and in silico analyses.