Submissions for variant NM_001754.5(RUNX1):c.98-2A>G

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV003448470	SCV004176257	likely pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2023-12-09	reviewed by expert panel	curation	The c.98-2A>G is a canonical splice site variant that is predicted to disrupt exon 4 acceptor splice site recognition (SpliceAI prediction: acceptor loss 0.75, at -2 bp), introduce exon 4 skipping, and produce a frameshift with a premature stop codon, resulting in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases (gnomAD v2.1 and v3.1) with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in three probands (PMID: 27288520, 29932212, and 36436542). They were diagnosed with myelodysplastic syndromes (one case) or acute myeloid leukemia (two cases). However, the germinal origin of the variant cannot be confirmed in any of them. In addition, another variant, the c.98-1G>A change, was discovered in a family with a patient who was diagnosed with an inherited platelet disorder. This latter has an impact on the same acceptor splice site and is likely to have the same effects on splicing (PMID: 32935436). 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, PM2_supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002851376	SCV003212258	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2022-06-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 3 of the RUNX1 gene. However, it is currently unclear if variants that occur in this region of the gene cause disease. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.