ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.292del (p.Leu98fs)

dbSNP: rs1569084170
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV003448332 SCV004176232 pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2023-12-09 reviewed by expert panel curation The NM_001754.5:c.292del p.(Leu98SerfsTer24) variant is a frameshift variant that is predicted to introduce a premature stop codon and is expected to result in nonsense-mediated mRNA decay. All the biologically relevant transcripts are predicted to be affected (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting), and is a nonsense variant downstream of c.98 (in transcript NM_001754.4) (PM5_supporting). The c.292del variant has been reported in one proband with a diagnosis of clonal cytopenia of undetermined significance (PMID: 33179473). This variant was identified by NGS and had a VAF of 33%. However, its germline origin was not assessed in the study. Therefore, we cannot assess case-study/segregation criteria. In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting.
PreventionGenetics, part of Exact Sciences RCV003892030 SCV000807770 pathogenic RUNX1-related disorder 2023-12-27 criteria provided, single submitter clinical testing The RUNX1 c.292delC variant is predicted to result in a frameshift and premature protein termination (p.Leu98Serfs*24). This variant has been reported in an individual with late-onset cytogenetically normal AML (Mendler et al. 2012. PubMed ID: 22753902. Table A2) and in a patient with AML and other chromosomal translocations (Auewarakul et al. 2007. PubMed ID: 17550866). This variant has also been reported in an individual with clonal cytopenia of undetermined significance (Mikkelsen et al. 2021. PubMed ID: 33179473. Table S2). This variant is interpreted as likely pathogenic or pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/561231/). Frameshift variants in RUNX1 are expected to be pathogenic. This variant is interpreted as pathogenic.
GeneDx RCV000680399 SCV002012655 pathogenic not provided 2020-06-05 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV001861880 SCV002245779 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2023-05-13 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 561231). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu98Serfs*24) in the RUNX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448).
Fulgent Genetics, Fulgent Genetics RCV002499199 SCV002810915 likely pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1; Acute myeloid leukemia 2022-02-01 criteria provided, single submitter clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV001861880 SCV003934871 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2022-06-10 criteria provided, single submitter curation Data included in classification: Absence from gnomAD v2.1.1 non-cancer WES data (PM2_sup) Frameshift variant downstream of c.98 in RUNX1 gene per RUNX1 VCEP guidance (PM5_sup) Myeloid NGS on bone marrow aspirate identified a RUNX1 frameshift variant with a VAF consistent with possible germline origin. Predicted to undergo nonsense-mediated decay (NMD). Exon present in all biologically relevant transcripts. Variant is in the region c.98- c.758 (PVS1_vs) Data not included in classification: 3x Pathogenic ClinVar classifications GeneDx ClinVar entry with germline allele origin and stated affected status COSMIC Variant Database shows 12 cases seen in Haem/Lymphoid Skokowa et al. 2014, 1x acquired (non-germline) case reported

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