ClinVar Miner

Submissions for variant NM_001001890.3(RUNX1):c.74T>A (p.Met25Lys) (rs200431130)

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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 RCV000231931 SCV000965651 uncertain significance Familial platelet disorder with associated myeloid malignancy 2019-07-26 reviewed by expert panel curation The NM_001754.4:c.155T>A (p.Met52Lys) variant has a MAF of 0.00071 (0.071%, 6/8,456 alleles) in the EA Allele subpopulation of the ESP cohort that is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense variant has a REVEL score >0.75 (0.845) (PP3). In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, PP3.
Invitae RCV000231931 SCV000287181 likely benign Familial platelet disorder with associated myeloid malignancy 2020-12-08 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000500073 SCV000596883 uncertain significance not specified 2017-03-10 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000680392 SCV000807763 uncertain significance not provided 2018-01-15 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761084 SCV000890999 uncertain significance Anaplastic ependymoma 2016-08-29 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000680392 SCV001552009 uncertain significance not provided no assertion criteria provided clinical testing The RUNX1 p.M52K variant was identified in the literature in two individuals with acute myeloid leukemia (Mendler_2013_PMID:23753029; Drazer_2018_PMID:29365323). The variant was identified in dbSNP (ID: rs200431130) and ClinVar (classified as uncertain significance by the ClinGen Myeloid Malignancy Variant Curation Expert Panel, Invitae, and three other laboratories). The variant was identified in control databases in 65 of 263936 chromosomes at a frequency of 0.0002463, and was observed at the highest frequency in the European (non-Finnish) population in 61 of 122518 chromosomes (freq: 0.0004979) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.M52 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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