Submissions for variant NM_001754.5(RUNX1):c.1228_1231dup (p.Ala411fs)

dbSNP: rs1569002077

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV001290700	SCV001478837	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). Although it has not been described, it is of note that 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, PM2_supporting, PM5_supporting.
PreventionGenetics, part of Exact Sciences	RCV000680385	SCV000807756	likely pathogenic	not provided	2015-06-25	criteria provided, single submitter	clinical testing