ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants

Xi Luo, Simone Feurstein, Shruthi Mohan, Christopher C. Porter, Sarah A. Jackson, Sioban Keel, Michael Chicka, Anna L. Brown, Chimene Kesserwan, Anupriya Agarwal, Minjie Luo, Zejuan Li, Justyne E. Ross, Panagiotis Baliakas, Daniel Pineda-Alvarez, Courtney D. DiNardo, Alison A. Bertuch, Nikita Mehta, Tom Vulliamy, Ying WangKim E. Nichols, Luca Malcovati, Michael F. Walsh, Lesley H. Rawlings, Shannon K. McWeeney, Jean Soulier, Anna Raimbault, Mark J. Routbort, Liying Zhang, Gabriella Ryan, Nancy A. Speck, Sharon E. Plon, David Wu, Lucy A. Godley

Research output: Contribution to journalArticle

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

Original languageEnglish
Pages (from-to)2962-2979
Number of pages18
JournalBlood advances
Volume3
Issue number20
DOIs
Publication statusPublished - Oct 22 2019

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Molecular Pathology
Genomics
Medical Genetics
Genome
Blood Platelets
Guidelines
Genes
Neoplasms
Hematologic Neoplasms
Gene Frequency
Acute Myeloid Leukemia
Thrombocytopenia
Patient Care
Phenotype

ASJC Scopus subject areas

  • Hematology

Cite this

Luo, X., Feurstein, S., Mohan, S., Porter, C. C., Jackson, S. A., Keel, S., ... Godley, L. A. (2019). ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants. Blood advances, 3(20), 2962-2979. https://doi.org/10.1182/bloodadvances.2019000644

ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants. / Luo, Xi; Feurstein, Simone; Mohan, Shruthi; Porter, Christopher C.; Jackson, Sarah A.; Keel, Sioban; Chicka, Michael; Brown, Anna L.; Kesserwan, Chimene; Agarwal, Anupriya; Luo, Minjie; Li, Zejuan; Ross, Justyne E.; Baliakas, Panagiotis; Pineda-Alvarez, Daniel; DiNardo, Courtney D.; Bertuch, Alison A.; Mehta, Nikita; Vulliamy, Tom; Wang, Ying; Nichols, Kim E.; Malcovati, Luca; Walsh, Michael F.; Rawlings, Lesley H.; McWeeney, Shannon K.; Soulier, Jean; Raimbault, Anna; Routbort, Mark J.; Zhang, Liying; Ryan, Gabriella; Speck, Nancy A.; Plon, Sharon E.; Wu, David; Godley, Lucy A.

In: Blood advances, Vol. 3, No. 20, 22.10.2019, p. 2962-2979.

Research output: Contribution to journalArticle

Luo, X, Feurstein, S, Mohan, S, Porter, CC, Jackson, SA, Keel, S, Chicka, M, Brown, AL, Kesserwan, C, Agarwal, A, Luo, M, Li, Z, Ross, JE, Baliakas, P, Pineda-Alvarez, D, DiNardo, CD, Bertuch, AA, Mehta, N, Vulliamy, T, Wang, Y, Nichols, KE, Malcovati, L, Walsh, MF, Rawlings, LH, McWeeney, SK, Soulier, J, Raimbault, A, Routbort, MJ, Zhang, L, Ryan, G, Speck, NA, Plon, SE, Wu, D & Godley, LA 2019, 'ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants', Blood advances, vol. 3, no. 20, pp. 2962-2979. https://doi.org/10.1182/bloodadvances.2019000644
Luo, Xi ; Feurstein, Simone ; Mohan, Shruthi ; Porter, Christopher C. ; Jackson, Sarah A. ; Keel, Sioban ; Chicka, Michael ; Brown, Anna L. ; Kesserwan, Chimene ; Agarwal, Anupriya ; Luo, Minjie ; Li, Zejuan ; Ross, Justyne E. ; Baliakas, Panagiotis ; Pineda-Alvarez, Daniel ; DiNardo, Courtney D. ; Bertuch, Alison A. ; Mehta, Nikita ; Vulliamy, Tom ; Wang, Ying ; Nichols, Kim E. ; Malcovati, Luca ; Walsh, Michael F. ; Rawlings, Lesley H. ; McWeeney, Shannon K. ; Soulier, Jean ; Raimbault, Anna ; Routbort, Mark J. ; Zhang, Liying ; Ryan, Gabriella ; Speck, Nancy A. ; Plon, Sharon E. ; Wu, David ; Godley, Lucy A. / ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants. In: Blood advances. 2019 ; Vol. 3, No. 20. pp. 2962-2979.
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AU - Luo, Xi

AU - Feurstein, Simone

AU - Mohan, Shruthi

AU - Porter, Christopher C.

AU - Jackson, Sarah A.

AU - Keel, Sioban

AU - Chicka, Michael

AU - Brown, Anna L.

AU - Kesserwan, Chimene

AU - Agarwal, Anupriya

AU - Luo, Minjie

AU - Li, Zejuan

AU - Ross, Justyne E.

AU - Baliakas, Panagiotis

AU - Pineda-Alvarez, Daniel

AU - DiNardo, Courtney D.

AU - Bertuch, Alison A.

AU - Mehta, Nikita

AU - Vulliamy, Tom

AU - Wang, Ying

AU - Nichols, Kim E.

AU - Malcovati, Luca

AU - Walsh, Michael F.

AU - Rawlings, Lesley H.

AU - McWeeney, Shannon K.

AU - Soulier, Jean

AU - Raimbault, Anna

AU - Routbort, Mark J.

AU - Zhang, Liying

AU - Ryan, Gabriella

AU - Speck, Nancy A.

AU - Plon, Sharon E.

AU - Wu, David

AU - Godley, Lucy A.

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