Submissions for variant NM_001754.5(RUNX1):c.799_800dup (p.Met267fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV003448471	SCV004176259	likely pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2023-12-09	reviewed by expert panel	curation	The NM_001754.5(RUNX1):c.799_800dup p.(Met267IlefsTer45) is a frameshift variant not expected to undergo nonsense-mediated mRNA decay. Nevertheless, the altered region is crucial for protein function, as it involves a duplication that impacts the established positions for frameshift (+1) variants (i.e., c.780-c.1440) (PVS1_Strong) and is positioned downstream of c.98 (in transcript NM_001754.4) (PM5_Supporting). This variant is entirely absent from all population databases (gnomAD v2.1.1, v3.1.2, and gnomAD v4.0.0) with at least 20x coverage for RUNX1 (PM2_supporting). To the best of our knowledge, this variant has not been reported in any study. In summary, this variant meets the 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, PM2_supporting, and PM5_supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002861546	SCV003214877	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2024-04-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met267Ilefs*45) in the RUNX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 214 amino acid(s) of the RUNX1 protein. 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. ClinVar contains an entry for this variant (Variation ID: 2014537). This variant disrupts a region of the RUNX1 protein in which other variant(s) (p.Arg320*) have been determined to be pathogenic (PMID: 18723428, 25840971, 31064749, 32208489). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.