Human Genetics Unit, Faculty of Medicine, University of Colombo, Colombo, 8, Sri Lanka.
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Bldg 560, Room 32-33, 1050 Boyles Street, Frederick, MD, 21702, USA.
Breast Cancer Res. 2020 May 11;22(1):43. doi: 10.1186/s13058-020-01272-z.
Next-generation sequencing of Sri Lankan families with inherited cancer syndromes resulted in the identification of five BRCA2 variants of unknown clinical significance. Interpreting such variants poses significant challenges for both clinicians and patients. Using a mouse embryonic stem cell-based functional assay, we found I785V, N830D, and K2077N to be functionally indistinguishable from wild-type BRCA2. Specific but mild sensitivity to olaparib and reduction in homologous recombination (HR) efficiency suggest partial loss of function of the A262T variant. This variant is located in the N-terminal DNA binding domain of BRCA2 that can facilitate HR by binding to dsDNA/ssDNA junctions. P3039P is clearly pathogenic because of premature protein truncation caused by exon 23 skipping. These findings highlight the value of mouse embryonic stem cell-based assays for determining the functional significance of variants of unknown clinical significance and provide valuable information regarding risk estimation and genetic counseling of families carrying these BRCA2 variants.
对斯里兰卡遗传性癌症综合征家族进行的下一代测序，发现了五个 BRCA2 种未知临床意义的变异。对这些变异的解释对临床医生和患者都构成了重大挑战。我们使用基于小鼠胚胎干细胞的功能测定，发现 I785V、N830D 和 K2077N 与野生型 BRCA2 在功能上无法区分。对奥拉帕利的特异性但轻度敏感性和同源重组 (HR) 效率的降低表明 A262T 变异具有部分功能丧失。该变异位于 BRCA2 的 N 端 DNA 结合结构域，通过与 dsDNA/ssDNA 连接结合促进 HR。P3039P 显然是致病性的，因为外显子 23 跳跃导致蛋白截短。这些发现强调了基于小鼠胚胎干细胞的测定在确定未知临床意义变异的功能意义方面的价值，并为携带这些 BRCA2 变异的家族的风险评估和遗传咨询提供了有价值的信息。
