Submissions for variant NM_001754.5(RUNX1):c.1345C>T (p.Gln449Ter)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV004701038	SCV005205687	likely pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2024-09-10	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.1345C>T (p.Gln449Ter) is a nonsense variant located downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). It is not expected to undergo nonsense-mediated decay, and the resulting frameshift affects positions c.759-c.1440 as per VCEP specifications, which are critical for protein function (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, and PM5_supporting.
GeneDx	RCV003327977	SCV004034762	uncertain significance	not provided	2023-03-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last 32 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge
CeGaT Center for Human Genetics Tuebingen	RCV003327977	SCV004153602	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	RUNX1: PM2, PVS1:Moderate