DICER1中的种系致病变异个体易患多种良性和恶性肿瘤。准确的变异筛选和分类对于DICER1相关肿瘤易感性的可靠诊断和识别可能从监测中受益的个体至关重要。自2015年以来,大多数实验室都遵循了美国医学遗传学和基因组学学院和分子病理学协会(ACMG/AMP)的DICER1种系变异筛选序列变异分类指南。然而,这些一般指南缺乏基因特异性的细微差别,并为主观性留下了空间。因此,一组DICER1专家加入ClinGen,组成了DICER1和miRNA加工基因变异固化专家组(VCEP),创建DICER1-特异性ACMG/AMP指南,用于种系变体管理。VCEP遵循FDA批准的ClinGen协议,以适应和试行这些指南。选择了40种DICER1变体进行试验,包括14种已知的致病性/可能致病性(P/LP)变体,12种已知的良性/可能良性(B/LB)变体,和14个变体分类为不确定意义(VUS)的变体或在ClinVar中具有相互矛盾的解释。临床意义的分类(即,P,LP,LB,或B)在82.5%(33/40)的试点变体中实现,在已知的P/LP和已知的B/LB变体之间具有100%一致性。一半的VUS或冲突变体被解决,其中四个变体被分类为LB,三个被分类为LP。这些结果表明,DICER1特定的种系变异管理指南有效地对已知的致病性和良性变异进行分类,同时降低了不确定分类的频率。策划DICER1变体的个人和实验室应考虑采用此分类框架,以鼓励一致性并提高客观性。
Germline pathogenic variants in DICER1 predispose individuals to develop a variety of benign and malignant tumors. Accurate variant curation and classification is essential for reliable diagnosis of DICER1-related tumor predisposition and identification of individuals who may benefit from surveillance. Since 2015, most labs have followed the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) sequence variant classification
guidelines for DICER1 germline variant curation. However, these general
guidelines lack gene-specific nuances and leave room for subjectivity. Consequently, a group of DICER1 experts joined ClinGen to form the DICER1 and miRNA-Processing Genes Variant Curation Expert Panel (VCEP), to create DICER1- specific ACMG/AMP
guidelines for germline variant curation. The VCEP followed the FDA-approved ClinGen protocol for adapting and piloting these
guidelines. A diverse set of 40 DICER1 variants were selected for piloting, including 14 known Pathogenic/Likely Pathogenic (P/LP) variants, 12 known Benign/Likely Benign (B/LB) variants, and 14 variants classified as variants of uncertain significance (VUS) or with conflicting interpretations in ClinVar. Clinically meaningful classifications (i.e., P, LP, LB, or B) were achieved for 82.5% (33/40) of the pilot variants, with 100% concordance among the known P/LP and known B/LB variants. Half of the VUS or conflicting variants were resolved with four variants classified as LB and three as LP. These results demonstrate that the DICER1-specific
guidelines for germline variant curation effectively classify known pathogenic and benign variants while reducing the frequency of uncertain classifications. Individuals and labs curating DICER1 variants should consider adopting this classification framework to encourage consistency and improve objectivity.