Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003448491 | SCV004176260 | likely pathogenic | Hereditary thrombocytopenia and hematologic cancer predisposition syndrome | 2023-12-09 | reviewed by expert panel | curation | The c.1256_1262dup (p.Glu422Glyfs*180)(NM_001754.5) variant is a frameshift duplication in RUNX1 - whose mechanism of disease is established to be loss-of-function - that is predicted to escape nonsense mediated decay but alter a functionally important region (transactivation domain, inhibitory domain, and/or the VWRPY motif) (PVS1_Strong). In addition, the variant is expected to result in a protein extension with a new stop codon at c.*351_*353, which is upstream of RUNX1's poly-A recognition and insertion sites (c.*3831_*3836 | c.*3850 and c.*4304_*4309 | c.*4334), and thus, non-stop decay is also not predicted. Furthermore, although this variant has not been published in patients, other pathogenic/likely pathogenic frameshift alterations in exon 8 have been reported (PMID: 35764482), and it may be of note that some RUNX1 frameshift elongation variants have been described with a dominant negative effect (PMID: 28855357) (PM5_Supporting). Finally, this variant is absent from gnomAD v2, v3, and v4 (PM2_Supporting). In summary, this variant meets the criteria to be classified as a likely pathogenic for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1_Strong, PM2_Supporting, and PM5_Supporting. (Version 2; date of approval) |
| Institute of Laboratory Medicine, |
RCV003232902 | SCV003929447 | pathogenic | Atypical chronic myeloid leukemia, BCR-ABL1 negative | 2022-04-20 | no assertion criteria provided | clinical testing |