Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants.
Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants.
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DOI：
10.1002/humu.22973
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发表时间：
2016-07
期刊：
影响因子：
3.9
通讯作者：
Tavtigian SV
中科院分区：
文献类型：
--
作者：
Vallée MP;Di Sera TL;Nix DA;Paquette AM;Parsons MT;Bell R;Hoffman A;Hogervorst FB;Goldgar DE;Spurdle AB;Tavtigian SV
癌症易感基因BRCA 1和BRCA 2的临床突变筛查产生许多未分类的变体（UV）。这些UV中的大多数是罕见的错义取代或蛋白质编码外显子的剪接点附近的核苷酸取代。之前，我们开发了一种用于评估BRCA基因UV的定量方法-“综合评估”-将基于序列分析的致病性先验概率与患者和/或肿瘤观察数据相结合，以获得致病性的后验概率。基于序列分析的先验的一个局限性是，它从错义取代严重性的角度评估UV，而不是从破坏正常mRNA剪接的概率的角度评估UV。在这里，我们校准了剪接位点适应性程序MaxEntScan的输出，以生成BRCA基因变异体基于剪接原性的致病性先验概率;这些概率范围从0.97（高概率损伤供体或受体的变异体）到0.02（不影响剪接点且不太可能产生从头供体的外显子变异体）。我们创建了一个数据库http://priors.hci.utah.edu/PRIORS/，该数据库提供了BRCA基因单核苷酸置换的合并错义置换严重性和基于剪接原性的致病性概率。我们还更新了BRCA基因Ex‐UV LOVD，可在http：//hci ‐exlovd.hci.utah.edu上获得，具有77个可重新评估的变体。
Clinical mutation screening of the cancer susceptibility genes BRCA1 and BRCA2 generates many unclassified variants (UVs). Most of these UVs are either rare missense substitutions or nucleotide substitutions near the splice junctions of the protein coding exons. Previously, we developed a quantitative method for evaluation of BRCA gene UVs—the “integrated evaluation”—that combines a sequence analysis‐based prior probability of pathogenicity with patient and/or tumor observational data to arrive at a posterior probability of pathogenicity. One limitation of the sequence analysis‐based prior has been that it evaluates UVs from the perspective of missense substitution severity but not probability to disrupt normal mRNA splicing. Here, we calibrated output from the splice‐site fitness program MaxEntScan to generate spliceogenicity‐based prior probabilities of pathogenicity for BRCA gene variants; these range from 0.97 for variants with high probability to damage a donor or acceptor to 0.02 for exonic variants that do not impact a splice junction and are unlikely to create a de novo donor. We created a database http://priors.hci.utah.edu/PRIORS/ that provides the combined missense substitution severity and spliceogenicity‐based probability of pathogenicity for BRCA gene single‐nucleotide substitutions. We also updated the BRCA gene Ex‐UV LOVD, available at http://hci‐exlovd.hci.utah.edu, with 77 re‐evaluable variants.