Specifications of the ACMG/AMP Variant Classification Guidelines for Germline DICER1 Variant Curation.

Autor: Hatton JN; Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA., Frone MN; Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA., Cox HC; PreventionGenetics LLC, Marshfield, Wisconsin, USA., Crowley SB; Invitae Corporation, San Francisco, California, USA., Hiraki S; GeneDx, Gaithersburg, Maryland, USA., Yokoyama NN; Ambry Genetics, Aliso Viejo, California, USA., Abul-Husn NS; Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Amatruda JF; Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA., Anderson MJ; Invitae Corporation, San Francisco, California, USA., Bofill-De Ros X; RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA., Carr AG; Weststat, Inc, Rockville, Maryland, USA., Chao EC; Ambry Genetics, Aliso Viejo, California, USA.; Division of Genetics and Genomics, Department of Pediatrics, University of California, Irvine, California, USA., Chen KS; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA., Gu S; RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA., Higgs C; Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA., Machado J; Exact Sciences Laboratories, Madison, Wisconsin, USA., Ritter D; Baylor College of Medicine, Houston, Texas, USA., Schultz KA; Cancer and Blood Disorders, Children's Minnesota, International Pleuropulmonary Blastoma/DICER1 Registry, Minneapolis, Minnesota, USA., Soper ER; Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Wu MK; Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA., Mester JL; GeneDx, Gaithersburg, Maryland, USA., Kim J; Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA., Foulkes WD; Department of Human Genetics, McGill University, Montreal, Quebec, Canada., Witkowski L; Department of Human Genetics, McGill University, Montreal, Quebec, Canada., Stewart DR; Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.
Jazyk: angličtina
Zdroj: Human mutation [Hum Mutat] 2023; Vol. 2023. Date of Electronic Publication: 2023 Mar 29.
DOI: 10.1155/2023/9537832
Abstrakt: 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.
Competing Interests: The following authors work for laboratories that offer fee-for-service testing of DICER1: MJA, ECC, HCC, SBC, SH, JM, JLM, NNY. The following authors have made substantial contributions to the DICER1 gene: disease literature: DRS, XB-D, KSC, WDF, SG, KAS, MKW. NSA-H is an employee and equity holder of 23andMe; serves as a scientific advisory board member for Allelica; received personal fees from Genentech, Allelica, and 23andMe; received research funding from Akcea; and was previously employed by Regeneron Pharmaceuticals.
Databáze: MEDLINE
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