Analysis of a set of missense, frameshift, and in-frame deletion variants of BRCA1.
Analysis of a set of missense, frameshift, and in-frame deletion variants of BRCA1.
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分析BRCA1的一组错义，移交和框内删除变体。
DOI：
10.1016/j.mrfmmm.2008.09.017
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发表时间：
2009-01-15
影响因子：
2.3
通讯作者：
Billack, Blase
中科院分区：
文献类型：
--
作者：
Carvalho, Marcelo;Pino, Maria A.;Karchin, Rachel;Beddor, Jennifer;Godinho-Netto, Martha;Mesquita, Rafael D.;Rodarte, Renato S.;Vaz, Danielle C.;Monteiro, Viviane A.;Manoukian, Siranoush;Colombo, Mara;Ripamonti, Carla B.;Rosenquist, Richard;Suthers, Graeme;Borg, Ake;Radice, Paolo;Grist, Scott A.;Monteiro, Alvaro N. A.;Billack, Blase
使 BRCA1 失活的种系突变是导致乳腺癌和卵巢癌易感性的原因。 BRCA1 基因检测的一个可能结果是发现了一种意义不确定的基因变异，目前还没有关于其癌症关联的信息。这一结果导致风险评估、咨询和预防保健方面出现问题。本研究的目的是对 BRCA1 的 7 个未分类变体进行功能评估，包括导致 mRNA 中外显子 16/17 (Δ 外显子 16/17) 框内丢失的基因组缺失、导致移码和羧基末端延长 (5673insC) 的插入，以及 5 个错义变体 (K1487R、S1613C、 M1652I、Q1826H 和 V1833M）。我们使用基于 BRCA1 转录激活特性的功能测定结合监督学习计算模型来分析变体。功能分析表明，变体 S1613C、Q1826H 和 M1652I 可能是中性变体，而变体 V1833M、Δ 外显子 16/17 和 5673insC 可能代表有害变体。与功能分析一致，计算分析的结果也表明后三种变体可能是有害的。总而言之，可以利用功能和生物信息学分析的组合方法以及结构建模来获得有关罕见变异对 BRCA1 结构和功能的影响的有价值的信息。反过来，此类信息可以帮助对缺乏提供可靠风险评估所需遗传信息的 BRCA1 变异进行分类。
Germline mutations that inactivate BRCA1 are responsible for breast and ovarian cancer susceptibility. One possible outcome of genetic testing for BRCA1 is the finding of a genetic variant of uncertain significance for which there is no information regarding its cancer association. This outcome leads to problems in risk assessment, counseling and preventive care. The purpose of the present study was to functionally evaluate seven unclassified variants of BRCA1 including a genomic deletion that leads to the in-frame loss of exons 16/17 (Δ exons 16/17) in the mRNA, an insertion that leads to a frameshift and an extended carboxy-terminus (5673insC), and five missense variants (K1487R, S1613C, M1652I, Q1826H and V1833M). We analyzed the variants using a functional assay based on the transcription activation property of BRCA1 combined with supervised learning computational models. Functional analysis indicated that variants S1613C, Q1826H, and M1652I are likely to be neutral, whereas variants V1833M, Δ exons 16/17, and 5673insC are likely to represent deleterious variants. In agreement with the functional analysis, the results of the computational analysis also indicated that the latter three variants are likely to be deleterious. Taken together, a combined approach of functional and bioinformatics analysis, plus structural modeling, can be utilized to obtain valuable information pertaining to the effect of a rare variant on the structure and function of BRCA1. Such information can, in turn, aid in the classification of BRCA1 variants for which there is a lack of genetic information needed to provide reliable risk assessment.
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影响因子：
9.8
作者：
Easton, Douglas F.;Deffenbaugh, Amie M.;Goldgar, David E.
通讯作者：
Goldgar, David E.
影响因子：
2.9
作者：
Karplus, K;Katzman, S;Hughey, R
通讯作者：
Hughey, R
DOI：
10.1073/pnas.94.11.5820
发表时间：
1997-05-27
影响因子：
11.1
作者：
Humphrey, JS;Salim, A;Klausner, RD
通讯作者：
Klausner, RD
影响因子：
11.2
作者：
Judkins, T;Hendrickson, BC;Scholl, T
通讯作者：
Scholl, T
DOI：
10.1089/10906570260199375
发表时间：
2002-06-01
期刊：
GENETIC TESTING
影响因子：
--
作者：
Deffenbaugh, AM;Frank, TS;Neuhausen, SL
通讯作者：
Neuhausen, SL