Specifications of the ACMG/AMP Variant Classification Guidelines for Germline DICER1 Variant Curation. (29th March 2023)

• Record Type: Journal Article
• Authors: Hatton, Jessica N.; Frone, Megan N.; Cox, Hannah C.; Crowley, Stephanie B.; Hiraki, Susan; Yokoyama, Noriko N.; Abul-Husn, Noura S.; Amatruda, James F.; Anderson, Michael J.; Bofill-De Ros, Xavier; Carr, Ann G.; Chao, Elizabeth C.; Chen, Kenneth S.; Gu, Shuo; Higgs, Cecilia; Machado, Jerry; Ritter, Deborah; Schultz, Kris Ann P.; Soper, Emily R.; Wu, Mona K.; Mester, Jessica L.; Kim, Jung; Foulkes, William D.; Witkowski, Leora; Stewart, Douglas R.
• Other Names: Chen Jian-Min Academic Editor.
• Is Part Of: Human mutation. Volume 2023(2023)
• Publication Date: 2023-03-29
• Subjects: Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1155/2023/9537832
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract : Germline pathogenic variants in DICER1 predispose individuals to develop a variety of benign and malignant tumors. Accurate variant curation and classification are essential for reliable diagnosis of DICER1- related tumor predisposition and the 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.