BRCA2 中意义不明变异的功能影响。
The functional impact of variants of uncertain significance in BRCA2.
机构信息
Department of Human Genetics, Leiden University Medical Center, PO Box 9600, Leiden, 2300RC, The Netherlands.
Department of Pathology, Leiden University Medical Center, PO Box 9600, Leiden, 2300RC, The Netherlands.
出版信息
Genet Med. 2019 Feb;21(2):293-302. doi: 10.1038/s41436-018-0052-2. Epub 2018 Jul 10.
PURPOSE
Genetic testing has uncovered large numbers of variants in the BRCA2 gene for which the clinical significance is unclear. Cancer risk prediction of these variants of uncertain significance (VUS) can be improved by reliable assessment of the extent of impairment of the tumor suppressor function(s) of BRCA2.
METHODS
Here, we evaluated the performance of the mouse embryonic stem cell (mESC)-based functional assay on an extensive set of BRCA2 missense variants.
RESULTS
Whereas all 20 nonpathogenic (class 1/2) variants were able to complement the cell lethal phenotype induced by loss of endogenous mouse Brca2, only 1 out of 15 pathogenic (class 4/5) variants (p.Gly2609Asp) was able to do so. However, in this variant the major tumor suppressive activity of BRCA2, i.e., homology directed repair (HDR), was severely abrogated. Among 43 evaluated VUS (class 3), 7 were unable to complement the lethal phenotype of mouse Brca2 loss while 7 other variants displayed a more severe reduction of HDR activity than observed for class 1/ 2 variants.
CONCLUSION
The mESC-based BRCA2 functional assay can reliably determine the functional impact of VUS, distinguish between pathogenic and nonpathogenic variants, and may contribute to improved cancer risk estimation for BRCA2 VUS carriers.
目的
基因检测已经发现了大量 BRCA2 基因中的变体，其临床意义尚不清楚。这些意义不明的变异体（VUS）的癌症风险预测可以通过可靠评估 BRCA2 的肿瘤抑制功能（s）的损伤程度来提高。
方法
在这里，我们评估了基于小鼠胚胎干细胞（mESC）的功能测定法在广泛的 BRCA2 错义变体中的性能。
结果
虽然所有 20 个非致病性（1/2 类）变体都能够弥补内源性小鼠 Brca2 缺失引起的细胞致死表型，但只有 15 个致病性（4/5 类）变体（p.Gly2609Asp）中的 1 个能够做到这一点。然而，在该变体中，BRCA2 的主要肿瘤抑制活性，即同源定向修复（HDR），严重受到了抑制。在 43 个评估的 VUS（3 类）中，有 7 个不能补充小鼠 Brca2 缺失的致死表型，而其他 7 个变体的 HDR 活性比 1/2 类变体严重降低。
结论
基于 mESC 的 BRCA2 功能测定法可以可靠地确定 VUS 的功能影响，区分致病性和非致病性变体，并可能有助于提高 BRCA2 VUS 携带者的癌症风险估计。
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