Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
J Med Genet. 2023 Dec 21;61(1):57-60. doi: 10.1136/jmg-2023-109433.
Despite the 2015 American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) guideline, many variants of gene remain inconclusive. In line with publication of the specific variant interpretation guideline by ClinGen in 2022, we reassessed variants of uncertain significance (VUS) in gene found in our institution.
VUS found in the course of sequencing between December 2015 and April 2022 were reassessed based on -specific variant interpretation guideline, review of updated literatures and additional genetic tests including family study and/or RNA study if available.
Out of 695 patients who underwent sequencing, 61 VUS were found in 69 patients. Among them, 38 VUS in 43 patients (62.3%) were reclassified as pathogenic and likely pathogenic variant ((L)PV), including 20 novel (L)PV. Major causes of reclassification were: (1) gene-specific modification of ACMG/AMP criteria, (2) updated literatures and (3) additional genetic tests. The most important evidence for reclassification was clarification of critical amino acid residues.
After reassessing variants according to -specific guideline and up-to-date database, a significant number of VUS was reclassified. Clinical laboratories are encouraged to perform variant reassessment at regular intervals or when there is a major change in the principle of variant interpretation.
尽管 2015 年美国医学遗传学与基因组学学院（ACMG）和分子病理学协会（AMP）指南已经发布，但仍有许多基因的变异结果不确定。为了与 2022 年 ClinGen 发布的特定变异解读指南保持一致，我们重新评估了本机构发现的基因中不确定意义的变异（VUS）。
根据特定的变异解读指南，重新评估了 2015 年 12 月至 2022 年 4 月期间在进行测序过程中发现的 VUS，并对最新文献进行了回顾，同时进行了其他遗传检测，包括家系研究和/或 RNA 研究（如果有条件）。
在接受 测序的 695 例患者中，有 69 例患者发现了 61 个 VUS。其中，43 例患者的 38 个 VUS（62.3%）被重新归类为致病性或可能致病性变异（(L)PV），包括 20 个新的 (L)PV。重新分类的主要原因是：（1）特定基因的 ACMG/AMP 标准修订，（2）最新文献，（3）其他遗传检测。重新分类最重要的依据是明确关键氨基酸残基。
根据特定指南和最新数据库对变异进行重新评估后，大量的 VUS 被重新归类。建议临床实验室定期或在变异解读原则发生重大变化时进行变异重新评估。
