文章：

丹麦疑似遗传性乳腺癌和/或卵巢癌易感人群的基因变异分类研究

Classification of Gene Variants in a Danish Population with Suspected Predisposition to Hereditary Breast and/or Ovarian Cancer

原文发布日期：29 May 2025

DOI: 10.3390/cancers17111819

类型: Article

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英文摘要：

Background: Gene variants of unknown significance (VUSs) present a challenge in genetic counselling. The primary aim of this study was to describe the spectrum of genetic findings in a cohort of 5923 Danish patients with suspected predisposition to hereditary breast and/or ovarian cancer, with a focus on classifying gene variants and investigating their distribution. Methods: The gene variants were classified using the American College of Medical Genetics (ACMG) guidelines as well as gene-specific guidelines where applicable. The identified VUSs were further examined through association analysis, comparison of the frequencies in this Danish population to those in the Swedish population using gnomAD 2.1, and splice analysis using RNA sequencing. Results: Of 167 variants that were clinically classified as VUSs prior to this research study, 38 (22.8%) were either up- or downgraded based on the guidelines that were used. We found that 630 patients (10.6%) carried a likely pathogenic or pathogenic variant, mainly inBRCA1(31.9%) andBRCA2(26.0%). VUSs were carried by 1606 (27.1%) patients, mainly inBARD1(27.6%) andATM(19.3%). Our association study assigned criteria for 10 gene variants, while our splice analysis assigned criteria for 3 gene variants but did not reclassify the variants. Conclusions: A total of 22.8% of the 167 variants that were observed in this study and which were previously classified as VUSs in a clinical setting were reclassified in this study. In total, 10.6% of the patients with a suspected predisposition to hereditary breast and/or ovarian cancer carried a likely pathogenic or pathogenic variant. The high incidence of VUSs observed in this study reflects the challenges faced in the daily clinical setting.

摘要翻译： 

背景：意义未明基因变异（VUS）给遗传咨询带来挑战。本研究主要目的是描述5923例疑似遗传性乳腺癌和/或卵巢癌易感性的丹麦患者队列的遗传学检测结果谱，重点在于基因变异分类及其分布特征分析。方法：采用美国医学遗传学与基因组学学会（ACMG）指南及适用情况下的基因特异性指南对基因变异进行分类。通过关联分析、使用gnomAD 2.1数据库比较丹麦与瑞典人群的变异频率、以及RNA测序剪接分析对VUS进行深入评估。结果：在研究前临床分类为VUS的167个变异中，38个（22.8%）根据指南标准进行了升级或降级重分类。630例患者（10.6%）携带可能致病或致病性变异，主要集中于BRCA1（31.9%）和BRCA2（26.0%）。1606例患者（27.1%）携带VUS，主要分布在BARD1（27.6%）和ATM（19.3%）。关联研究为10个基因变异提供了分类依据，剪接分析为3个基因变异提供了证据但未实现重分类。结论：本研究中观察到的167个既往临床分类为VUS的变异，有22.8%在本研究中实现重分类。总计10.6%的疑似遗传性乳腺癌和/或卵巢癌易感患者携带可能致病或致病性变异。本研究观察到的高VUS发生率反映了临床日常工作中面临的挑战。

原文链接：

Classification of Gene Variants in a Danish Population with Suspected Predisposition to Hereditary Breast and/or Ovarian Cancer