ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.422_423insATACCTTCGGACAAGGGGAATCGGAATAAAAG (p.Ala142fs)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV004700851 SCV005205668 pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-08-28 reviewed by expert panel curation NM_001754.5(RUNX1):c.422_423insATACCTTCGGACAAGGGGAATCGGAATAAAAG (p.Ala142TyrfsTer14) is a frameshift variant which is predicted to undergo nonsense-mediated decay in a gene in which loss-of-function is an established mechanism (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; PMID: 31709191). In summary, this variant meets 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, PS4_supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV002863808 SCV003235295 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2022-11-01 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala142Tyrfs*14) 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).

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