How I curate: applying American Society of Hematology-Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel rules for <i>RUNX1</i> variant curation for germline predisposition to myeloid malignancies

Wu, David; Luo, Xi; Feurstein, Simone; Kesserwan, Chimene; Mohan, Shruthi; Pineda-Álvarez, Daniel E.; Godley, Lucy A.

doi:10.3324/haematol.2018.214221

“…Curation rules for germline RUNX1 variants are available from the Myeloid Malignancy Variant Curation Expert Panel (clinicalgenome.org/affiliation/50034/) and are being applied to RUNX1 variants within ClinVar with U.S. Food and Drug Administration recognition. 10,11 The ClinGen curation process undergoes reassessment every 2 years to allow updating based on recent literature and revised ClinGen recommendations.…”

Section: Identifying Potential Germline Alterationsmentioning

confidence: 99%

Identifying potential germline variants from sequencing hematopoietic malignancies

Kraft

¹

,

Godley

²

2020

Self Cite

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Next-generation sequencing (NGS) of bone marrow and peripheral blood increasingly guides clinical care in hematological malignancies. NGS data may help to identify single nucleotide variants, insertions/deletions, copy number variations, and translocations at a single time point, and repeated NGS testing allows tracking of dynamic changes in variants during the course of a patient’s disease. Tumor cells used for NGS may contain germline, somatic, and clonal hematopoietic DNA alterations, and distinguishing the etiology of a variant may be challenging. We describe an approach using patient history, individual variant characteristics, and sequential NGS assays to identify potential germline variants. Our current criteria for identifying an individual likely to have a deleterious germline variant include a strong family history or multiple cancers in a single patient, diagnosis of a hematopoietic malignancy at a younger age than seen in the general population, variant allele frequency > 0.3 of a deleterious allele in a known germline predisposition gene, and variant persistence identified on clinical NGS panels, despite a change in disease state. Sequential molecular testing of hematopoietic specimens may provide insight into disease pathology, impact patient and family members’ care, and potentially identify new cancer-predisposing risk alleles. Ideally, individuals should give consent at the time of NGS testing to receive information about potential germline variants and to allow future contact as research advances.

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“…The appropriate curation of gene variants associated with diseases is considered very relevant and is currently underway by the Clinical Genome Resource (ClinGen) with the Variant Curation Expert Panels. Since, in contrast to GT 33 and RUNX1 related disease, 34,35 interpretation rules for variants involved in TUBB1-RT have not been generated yet, it is highly warranted that this curation is made by a ClinGen expert panel.…”

Section: Discussionmentioning

confidence: 99%

“…The guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), 32 to assess the pathogenicity of the TUBB1 variants before and after taking into account the results of the current study, were followed. It should however be noted that to date, specific ACGM/AMP rules for IPD different from Glanzmann Thrombasthenia (GT) 33 and RUNX1-related disease 34,35 have not been reported. Therefore, we adapted the ACGM criteria to the classification of TUBB1 variants of our patients as specified in the legend of Supplemental Table S3.…”

Section: Molecular Analysis By Hts Gene Panel and Sanger Sequencingmentioning

confidence: 99%

Expanding the genetic spectrum of TUBB1-related thrombocytopenia

Palma-Barqueros

¹

,

Bury

²

,

Kunishima

³

et al. 2021

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β1-tubulin plays a major role in proplatelet formation and platelet shape maintenance, and pathogenic variants in TUBB1 lead to thrombocytopenia and platelet anisocytosis (TUBB1-RT). To date, the reported number of pedigrees with TUBB1-RT and of rare TUBB1 variants with experimental demonstration of pathogenicity is limited. Here, we report 9 unrelated families presenting with thrombocytopenia carrying six β1-tubulin variants: p.Cys12Leufs12*, p.Thr107Pro, p.Gln423*, p.Arg359Trp, p.Gly109Glu, and p.Gly269Asp, the last of which novel. Segregation studies showed incomplete penetrance of these variants for platelet traits. Indeed, most carriers showed macrothrombocytopenia, some only increased platelet size and a minority no abnormalities. Moreover, only homozygous carriers of the p.Gly109Glu variant, displayed macrothrombocytopenia, highlighting the importance of allele burden in the phenotypic expression of TUBB1-RT. The p.Arg359Trp, p.Gly269Asp and p.Gly109Glu variants deranged β1-tubulin incorporation into the microtubular marginal ring in platelets, while had negligible effect on platelet activation, secretion or spreading, suggesting that β1-tubulin is dispensable for these processes. Transfection of TUBB1 missense variants in CHO cells altered β1-tubulin incorporation into the microtubular network. In addition, TUBB1 variants markedly impaired proplatelet formation from peripheral blood CD34+ cell-derived megakaryocytes. Our study, using in vitro modeling, molecular characterization, and clinical investigations provides a deeper insight into the pathogenicity of rare TUBB1 variants. These novel data expand the genetic spectrum of TUBB1-RT and highlight a remarkable heterogeneity in its clinical presentation, indicating that allelic burden or combination with other genetic or environmental factors modulate the phenotypic impact of rare TUBB1 variants.

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“…Curation rules for germline RUNX1 variants are available from the Myeloid Malignancy Variant Curation Expert Panel (clinicalgenome.org/affiliation/50034/) and are being applied to RUNX1 variants within ClinVar with U.S. Food and Drug Administration recognition. 10,11 The ClinGen curation process undergoes reassessment every 2 years to allow updating based on recent literature and revised ClinGen recommendations. Identifying potential germline alleles from NGS assays of tumor samples…”

Section: Identifying Potential Germline Alterationsmentioning

confidence: 99%

Identifying potential germline variants from sequencing hematopoietic malignancies

Kraft

¹

,

Godley

²

2020

Blood

Self Cite

View full text Add to dashboard Cite

Next-generation sequencing (NGS) of bone marrow and peripheral blood increasingly guides clinical care in hematological malignancies. NGS data may help to identify single nucleotide variants, insertions/deletions, copy number variations, and translocations at a single time point, and repeated NGS testing allows tracking of dynamic changes in variants during the course of a patient’s disease. Tumor cells used for NGS may contain germline, somatic, and clonal hematopoietic DNA alterations, and distinguishing the etiology of a variant may be challenging. We describe an approach using patient history, individual variant characteristics, and sequential NGS assays to identify potential germline variants. Our current criteria for identifying an individual likely to have a deleterious germline variant include a strong family history or multiple cancers in a single patient, diagnosis of a hematopoietic malignancy at a younger age than seen in the general population, variant allele frequency > 0.3 of a deleterious allele in a known germline predisposition gene, and variant persistence identified on clinical NGS panels, despite a change in disease state. Sequential molecular testing of hematopoietic specimens may provide insight into disease pathology, impact patient and family members’ care, and potentially identify new cancer-predisposing risk alleles. Ideally, individuals should give consent at the time of NGS testing to receive information about potential germline variants and to allow future contact as research advances.

show abstract

How I curate: applying American Society of Hematology-Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel rules for RUNX1 variant curation for germline predisposition to myeloid malignancies

Cited by 25 publications

References 83 publications

Identifying potential germline variants from sequencing hematopoietic malignancies

Identifying potential germline variants from sequencing hematopoietic malignancies

Expanding the genetic spectrum of TUBB1-related thrombocytopenia

Identifying potential germline variants from sequencing hematopoietic malignancies

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