Submissions for variant NM_001754.5(RUNX1):c.356dup (p.Ala120fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV004701752	SCV005205616	likely pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2024-08-28	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.356dup (p.Ala120GlyfsTer18) is a frameshift variant which is not predicted to undergo nonsense-mediated decay (NMD), and the truncated/altered region is critical for protein function (PVS1_Strong). This variant is downstream of c.98 (PM5_supporting). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in at least two probands meeting RUNX1-phenotypic criteria (PS4_Moderate). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM5_supporting, PM2_supporting, PS4_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003514840	SCV004309346	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2023-08-18	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala120Glyfs*18) 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 has not been reported in the literature in individuals affected with RUNX1-related conditions. For these reasons, this variant has been classified as Pathogenic.