使用临床和功能数据重新分类两种不确定的MLH1变异
Jane Hübertz Frederiksen1, Ulf Birkedal1, Sarah Bachmann1
1Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Molecular genetics & genomic medicine
|November 15, 2024
概括
两种MLH1基因变异,以前不确定,现在被归类为可能致病的. 这种重新分类有助于对具有这些变异的家族进行结直肠癌风险评估.
科学领域:
- 遗传学 是一个遗传学.
- 在瘤学瘤学.
- 分子生物学分子生物学
背景情况:
- 不匹配修复基因中的致病变体增加了结直肠癌 (CRC) 的风险.
- 两种MLH1基因变异 (c.696_698del,p.(Cys233del) 和c.1919C > G,p.(Pro640Arg)) 之前被确定为在丹麦家庭中具有高CRC发病率的不确定的意义 (VUS) 的变异.
研究的目的:
- 为了重新分类两个已识别的MLH1变种的VUS状态.
- 改进携带这些变体的家庭对结直肠癌的遗传风险评估.
主要方法:
- 收集了临床数据,并启动了瘤和同分离分析.
- 进行了RNA拼接分析,亚细胞定位和蛋白质稳定性研究.
- 应用不匹配修复 (MMR) 基因特异性ACMG/AMP变异重新分类的指导方针.
主要成果:
- 功能分析表明c.696_698del,p.(Cys233del) 影响RNA,亚细胞局部化和蛋白质稳定性.
- c.1919C > G,p.(Pro640Arg) 变种显示表达和蛋白质稳定性下降.
- 建议这两种变体都会破坏DNA不匹配修复过程.
结论:
- 建议MLH1变种c.696_698del,p.(Cys233del) 和c.1919C > G,p.(Pro640Arg) 重新归类为可能致病性 (第4类).
- 这种重新分类可以对变种载体进行准确的风险评估.
- 没有这些变异的家庭成员可以被排除在加强癌症监测之外,优化医疗保健资源分配.
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