Submissions for variant NM_001754.5(RUNX1):c.132dup (p.Thr45fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV004701089	SCV005205683	pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2024-09-10	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.132dup (p.Thr45HisfsTer?) is a frameshift variant which is predicted to undergo nonsense-mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98-c.779 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is downstream of c.98 (PM5_Supporting). In summary, this variant meets 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003515504	SCV004368138	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr45Hisfs*93) in the RUNX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. For these reasons, this variant has been classified as Pathogenic.