Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000540519 | SCV000965662 | pathogenic | Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 | 2019-08-06 | reviewed by expert panel | curation | The deletion of exons 1 (non-coding) and 2 or exons 1, 2, and 3, all affecting presumedly exclusively RUNX1 isoform C, are common in FPD/AML patients and currently represent the most common pathogenic CNV in RUNX1. Multiple probands have been reported. These deletions only affect the N-terminal region of isoform C which is not shared by isoforms A and B. Despite the N-terminal region being a functionally unknown part of the protein, isoform C is biologically important und deletions are absent in the population which warrants application of PVS1_Moderate and PM2. Probands and affected family members show the typical FPD/AML phenotype and the deletion segregates with disease in multiple affected family members across multiple families (PP1_Strong). In addition, PS4 can be applied due to 5 probands with FPD/AML were reported from internal laboratories. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS4, PP1_Strong, PVS1_Moderate, PM2. |
| Labcorp Genetics |
RCV000540519 | SCV000638119 | pathogenic | Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 | 2017-03-06 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exon 2 of the RUNX1 gene, which includes the initiator codon. The 5' end of this event is unknown as it extends beyond the assayed region for this gene and therefore may encompass additional genes. The 3' boundary is likely confined to intron 2 of the RUNX1 gene. This is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448). For these reasons, this variant has been classified as Pathogenic. |