We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case-control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls.
A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)-like (N = 226). We then examined their association with breast cancer risk in the case-control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35-3.41), 1.57 (95% CI, 1.41-1.75), and 1.19 (95% CI, 1.08-1.31), respectively. The meta-analysis of population-specific datasets showed similar results.
We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.
■我们在15个国家收集了由ENIGMA联盟确定的460个CHEK2错觉VUS。使用CHEK2互补测定定量人RPE1-CHEK2敲除细胞中的KAP1磷酸化和CHK2自磷酸化进行其功能表征。两种功能测定的一致结果用于从12个ENIGMA病例对照数据集中对CHEK2VUS进行分类,包括73,048名女性乳腺癌患者和88,658名种族匹配的对照。
■总共成功分析了430/460VUS,其中340(79.1%)在两种功能测定中均一致,并归类为功能受损(N=102),功能中间(N=12),或功能野生型(WT)样(N=226)。然后,我们在病例对照分析中检查了它们与乳腺癌风险的关联。功能受损携带者的OR和95%CI(置信区间),中间,WT样变异为2.83(95%CI,2.35-3.41),1.57(95%CI,1.41-1.75),和1.19(95%CI,1.08-1.31),分别。对特定人群数据集的荟萃分析显示出类似的结果。
■我们确定了在乳腺癌患者中发现的大多数CHEK2错义VUS的功能后果(3,660/4,436;82.5%)。功能性受损错义变异的携带者占乳腺癌患者的0.5%,并且与截短CHEK2变异的中等风险相似。相比之下,所有乳腺癌患者中有2.2%携带功能野生型/中间错义变异,在杂合子携带者中没有临床相关的乳腺癌风险。