Submissions for variant NM_001754.5(RUNX1):c.802C>T (p.Gln268Ter)

dbSNP: rs2146074437

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV003448449	SCV004176233	pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2023-12-09	reviewed by expert panel	curation	The NM_001754.5(RUNX1):c.802C>T (p.Gln268Ter) is a nonsense variant that is predicted to cause a premature stop codon in biologically-relevant exon 7/9 which is present in all biologically transcripts. The variant is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (nonsense c.98-c.916 as per VCEP specifications) (PVS1).This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This nonsense variant is downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 36736831). The same case was proven to be de novo (PS2_Supporting). In summary, this variant meets the 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, PM5_supporting, PS2_supporting, PS4_supporting.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002245413	SCV002515654	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1		criteria provided, single submitter	clinical testing