ClinVar Miner

Submissions for variant NM_001754.4(RUNX1):c.508+2T>C (rs1601515707)

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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 RCV001195662 SCV001366058 likely pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2020-03-18 reviewed by expert panel curation The NM_001754.4:c.508+2T>C variant is a donor splice site variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). Two patients reported with this variant in the literature do not meet criteria for PS4 (PMID: 30520015; 29296763). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2.
Invitae RCV000796520 SCV000936038 likely pathogenic Familial platelet disorder with associated myeloid malignancy 2018-12-12 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the RUNX1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RUNX1-related conditions. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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