Submissions for variant NM_001754.5(RUNX1):c.891_904del (p.Pro298fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV005001423	SCV005627433	likely pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2025-01-15	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.891_904del (p.Pro298Phefs*297) is a frameshift variant in biologically relevant exon 8/9, predicted to alter the C-terminus of the protein, a region critical to protein function (transactivation domain, inhibitory domain, and/or the VWRPY motif) (PVS1_Strong). This variant is absent from gnomAD v2, v3, and v4 (PM2_supporting). Although the variant has not been reported in the literature, other nonsense/frameshift variants in exon 8 have been reported as pathogenic/likely pathogenic (PMID: 35764482) (PM5_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1, PM2_supporting, and PM5_supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003630711	SCV004504903	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2023-02-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the RUNX1 gene (p.Pro298Phefs*297). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 183 amino acid(s) of the RUNX1 protein and extend the protein by 113 additional amino acid residues.