ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.1198_1201dup (p.Pro401fs)

dbSNP: rs1569002159
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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 RCV001290708 SCV001478845 likely pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-06-24 reviewed by expert panel curation This late duplication which results in a frameshift is not expected to result in nonsense mediated mRNA decay, but will alter the transactivation domain/inhibitory domain/VWRPY motif and elongate the protein (PVS1_strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a frameshift variant that is downstream of c.98 (PM5_Supporting). It has been described in a patient with thrombocytopenia (personal communication with last author) and short telomeres (<1st percentile), but the variant could not be confirmed in the germline (PMID: 29463756). However, other C-terminal frameshift variants have been reported with some showing loss of transactivation ability and a dominant-negative effect (PMID: 14615365, 19808697, 25840971). In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong and PM2_supporting, PM5_supporting.
PreventionGenetics, part of Exact Sciences RCV000680384 SCV000807755 likely pathogenic not provided 2018-07-12 criteria provided, single submitter clinical testing

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