ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants Guidelines
| Authors: | Luo, X.; Feurstein, S.; Mohan, S.; Porter, C. C.; Jackson, S. A.; Keel, S.; Chicka, M.; Brown, A. L.; Kesserwan, C.; Agarwal, A.; Luo, M.; Li, Z.; Ross, J. E.; Baliakas, P.; Pineda-Alvarez, D.; DiNardo, C. D.; Bertuch, A. A.; Mehta, N.; Vulliamy, T.; Wang, Y.; Nichols, K. E.; Malcovati, L.; Walsh, M. F.; Rawlings, L. H.; McWeeney, S. K.; Soulier, J.; Raimbault, A.; Routbort, M. J.; Zhang, L.; Ryan, G.; Speck, N. A.; Plon, S. E.; Wu, D.; Godley, L. A. |
| Title: | ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants |
| Abstract: | Standardized variant curation is essential for clinical care recommendations for patients with inherited disorders. Clinical Genome Resource (ClinGen) variant curation expert panels are developing disease-associated gene specifications using the 2015 American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines to reduce curation discrepancies. The ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) was created collaboratively between the American Society of Hematology and ClinGen to perform gene- and disease-specific modifications for inherited myeloid malignancies. The MM-VCEP began optimizing ACMG/AMP rules for RUNX1 because many germline variants have been described in patients with familial platelet disorder with a predisposition to acute myeloid leukemia, characterized by thrombocytopenia, platelet functional/ultrastructural defects, and a predisposition to hematologic malignancies. The 28 ACMG/AMP codes were tailored for RUNX1 variants by modifying gene/disease specifications, incorporating strength adjustments of existing rules, or both. Key specifications included calculation of minor allele frequency thresholds, formulating a semi-quantitative approach to counting multiple independent variant occurrences, identifying functional domains and mutational hotspots, establishing functional assay thresholds, and characterizing phenotype-specific guidelines. Preliminary rules were tested by using a pilot set of 52 variants; among these, 50 were previously © 2019 by The American Society of Hematology |
| Keywords: | promoter region; single nucleotide polymorphism; phenotype; gene; cancer susceptibility; thrombocytopenia; genetic variability; gene frequency; practice guideline; acute lymphoblastic leukemia; hematologic malignancy; myelodysplastic syndrome; alternative rna splicing; transcription factor runx1; genotype phenotype correlation; acute myeloid leukemia; indel mutation; thrombocyte disorder; human; priority journal; article; runx1 gene |
| Journal Title: | Blood Advances |
| Volume: | 3 |
| Issue: | 20 |
| ISSN: | 2473-9529 |
| Publisher: | American Society of Hematology |
| Date Published: | 2019-10-22 |
| Start Page: | 2962 |
| End Page: | 2979 |
| Language: | English |
| DOI: | 10.1182/bloodadvances.2019000644 |
| PUBMED: | 31648317 |
| PROVIDER: | scopus |
| PMCID: | PMC6849945 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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