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Integration of functional assay data results provides strong evidence for classification of hundreds of BRCA1 variants of uncertain significance
Genetics in Medicine ( IF 8.8 ) Pub Date : 2020-10-22 , DOI: 10.1038/s41436-020-00991-0
Paulo C M Lyra 1 , Thales C Nepomuceno 2, 3, 4 , Marcele L M de Souza 1 , Géssica F Machado 1 , Mariana F Veloso 1 , Taciane B Henriques 1 , Diandra Z Dos Santos 1 , Iuly G Ribeiro 1 , Roberto S Ribeiro 1 , Leticia B A Rangel 1 , Marcy Richardson 5 , Edwin S Iversen 6 , David Goldgar 7 , Fergus J Couch 8 , Marcelo A Carvalho 2, 9 , Alvaro N A Monteiro 4
Affiliation  

Purpose

BRCA1 pathogenic variant heterozygotes are at a substantially increased risk for breast and ovarian cancer. The widespread uptake of testing has led to a significant increase in the detection of missense variants in BRCA1, the vast majority of which are variants of uncertain clinical significance (VUS), posing a challenge to genetic counseling. Here, we harness a wealth of functional data for thousands of variants to aid in variant classification.

Methods

We have collected, curated, and harmonized functional data for 2701 missense variants representing 24.5% of possible missense variants in BRCA1. Results were harmonized across studies by converting data into binary categorical variables (functional impact versus no functional impact). Using a panel of reference variants we identified a subset of assays with high sensitivity and specificity (≥80%) and apply the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant interpretation guidelines to assign evidence criteria for classification.

Results

Integration of data from validated assays provided ACMG/AMP evidence criteria in favor of pathogenicity for 297 variants or against pathogenicity for 2058 representing 96.2% of current VUS functionally assessed. We also explore discordant results and identify limitations in the approach.

Conclusion

High quality functional data are available for BRCA1 missense variants and provide evidence for classification of 2355 VUS according to their pathogenicity.



中文翻译:

功能测定数据结果的整合为数百个意义不确定的 BRCA1 变体的分类提供了强有力的证据

目的

BRCA1致病性变异杂合子患乳腺癌和卵巢癌的风险显着增加。检测的广泛采用导致BRCA1中错义变异的检测显着增加,其中绝大多数是临床意义不确定的变异 (VUS),对遗传咨询提出了挑战。在这里,我们利用数千个变体的大量功能数据来帮助进行变体分类。

方法

我们收集、整理和协调了 2701 个错义变体的功能数据,占BRCA1中可能错义变体的 24.5% 。通过将数据转换为二元分类变量(功能影响与无功能影响),研究结果得到了协调。使用一组参考变体,我们确定了一个具有高灵敏度和特异性 (≥80%) 的分析子集,并应用美国医学遗传学和基因组学/分子病理学协会 (ACMG/AMP) 变体解释指南来分配证据标准分类。

结果

来自经过验证的化验数据的整合提供了 ACMG/AMP 证据标准,支持 297 种变体的致病性或反对 2058 年的致病性,占当前 VUS 功能评估的 96.2%。我们还探索了不一致的结果并确定了该方法的局限性。

结论

高质量的功能数据可用于BRCA1错义变异,并为根据其致病性对 2355 VUS 进行分类提供证据。

更新日期:2020-10-28
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