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

dbSNP: rs1569084170

Total submissions: 6

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