Comparison of RUNX1 variant curation between the study by Simon et al and the MM-VCEP
ID* . | Variant cDNA/protein* . | Described in MDS/AML* . | Described in RUNX1 FPD* . | Functional impact on RUNX1* . | MM-VCEP ACMG/AMP criteria code* . | MM-VCEP RUNX1-specific criteria† . | Further explanation of criteria† . | MM-VCEP classification† . |
---|---|---|---|---|---|---|---|---|
1 | c.44_45delAG/p.Q15fsX | — | — | Truncating | PVS1_moderate, PS4_supporting, PM2 | PS4_supporting, PM2 | PVS1 cannot be used for early truncating variants only affecting RUNX1 isoform C. | VUS |
2 | c.179C>T/p.A60V | Carnicer et al23 | Lorente24 | — | BS1 | BS1, BS3 | This variant meets the calculated BS1 threshold (Latino subpopulation) and BS3 (normal transactivation and normal DNA binding/subcellular localization).25 The presence of the variant in patients with a RUNX1 phenotype is not sufficient to call a variant PATH, in particular not if the variant is present in gnomAD at a MAF incompatible with disease prevalence. | BEN |
3+4‡ | c.421T>G/p.S141A | — | RUNX1db | Normal transactivation26 | PS4_supporting, PP3, BS3_supporting | PM1_supporting, PP3 | Variant not present in RUNX1db. Although there is no effect on heterodimerization ability with CBF,26 data from an additional secondary assay or transactivation assay are missing; this does not permit application of any BS3 strength level. PS4 cannot be applied (2 alleles in gnomAD). | VUS |
5 | c.427G>T/p.E143X | — | — | Truncating | PVS1, PS4_supporting, PM2 | PVS1, PS4_supporting, PM2 | PATH | |
6 | c.454_456insA/p.K152fsX | Ernst et al27 | — | Truncating | PVS1, PS4_supporting, PM2 | PVS1, PS4_supporting, PM2 | Variant nomenclature does not conform with HGVS recommendations for sequence variants. We assume this variant is not present in gnomAD (PM2) and leads to NMD (PVS1). | PATH |
7 | c.496C>G/p.R166G | Imai et al28 | — | LOF/dominant negative28 | PS4_supporting, PM2, PM5, PP3 | PS4_supporting, PM1, PM2, PM5, PP3 | R166Q has been curated by the MM-VCEP as PATH. | LPATH |
8 | c.496C>T/p.R166X | Preudhomme et al29 | Bluteau et al30 | Truncating | PVS1, PS4, PM2, PP1 | PVS1, PS4, PM2, PP1_strong | PATH | |
9+10 | c.610C>T/p.R204X | Osato et al31 | Song et al32 | LOF31 | PVS1, PS4, PM2, PP1 | PVS1, PS4, PM2, PP1_strong | PATH | |
11 | c.619C>T/p.R207W | You et al33 | — | — | PS4_supporting, PM2, PP3 | PS4_moderate, PM2, PP3 | In silico prediction alone (ie, in this case pathogenic predictions by using SIFT, Polyphen, VEST, CHASM, and REVEL) is only supporting evidence and insufficient to classify a variant as PATH. | VUS |
12 | c.1243_1244insC/p.Q415fsX | — | — | Elongated RUNX1 isoform | PVS1_strong, PS4_supporting, PM2 | PVS1_strong, PS4_supporting, PM2 | LPATH |
ID* . | Variant cDNA/protein* . | Described in MDS/AML* . | Described in RUNX1 FPD* . | Functional impact on RUNX1* . | MM-VCEP ACMG/AMP criteria code* . | MM-VCEP RUNX1-specific criteria† . | Further explanation of criteria† . | MM-VCEP classification† . |
---|---|---|---|---|---|---|---|---|
1 | c.44_45delAG/p.Q15fsX | — | — | Truncating | PVS1_moderate, PS4_supporting, PM2 | PS4_supporting, PM2 | PVS1 cannot be used for early truncating variants only affecting RUNX1 isoform C. | VUS |
2 | c.179C>T/p.A60V | Carnicer et al23 | Lorente24 | — | BS1 | BS1, BS3 | This variant meets the calculated BS1 threshold (Latino subpopulation) and BS3 (normal transactivation and normal DNA binding/subcellular localization).25 The presence of the variant in patients with a RUNX1 phenotype is not sufficient to call a variant PATH, in particular not if the variant is present in gnomAD at a MAF incompatible with disease prevalence. | BEN |
3+4‡ | c.421T>G/p.S141A | — | RUNX1db | Normal transactivation26 | PS4_supporting, PP3, BS3_supporting | PM1_supporting, PP3 | Variant not present in RUNX1db. Although there is no effect on heterodimerization ability with CBF,26 data from an additional secondary assay or transactivation assay are missing; this does not permit application of any BS3 strength level. PS4 cannot be applied (2 alleles in gnomAD). | VUS |
5 | c.427G>T/p.E143X | — | — | Truncating | PVS1, PS4_supporting, PM2 | PVS1, PS4_supporting, PM2 | PATH | |
6 | c.454_456insA/p.K152fsX | Ernst et al27 | — | Truncating | PVS1, PS4_supporting, PM2 | PVS1, PS4_supporting, PM2 | Variant nomenclature does not conform with HGVS recommendations for sequence variants. We assume this variant is not present in gnomAD (PM2) and leads to NMD (PVS1). | PATH |
7 | c.496C>G/p.R166G | Imai et al28 | — | LOF/dominant negative28 | PS4_supporting, PM2, PM5, PP3 | PS4_supporting, PM1, PM2, PM5, PP3 | R166Q has been curated by the MM-VCEP as PATH. | LPATH |
8 | c.496C>T/p.R166X | Preudhomme et al29 | Bluteau et al30 | Truncating | PVS1, PS4, PM2, PP1 | PVS1, PS4, PM2, PP1_strong | PATH | |
9+10 | c.610C>T/p.R204X | Osato et al31 | Song et al32 | LOF31 | PVS1, PS4, PM2, PP1 | PVS1, PS4, PM2, PP1_strong | PATH | |
11 | c.619C>T/p.R207W | You et al33 | — | — | PS4_supporting, PM2, PP3 | PS4_moderate, PM2, PP3 | In silico prediction alone (ie, in this case pathogenic predictions by using SIFT, Polyphen, VEST, CHASM, and REVEL) is only supporting evidence and insufficient to classify a variant as PATH. | VUS |
12 | c.1243_1244insC/p.Q415fsX | — | — | Elongated RUNX1 isoform | PVS1_strong, PS4_supporting, PM2 | PVS1_strong, PS4_supporting, PM2 | LPATH |
All variants are annotated using RefSeq ID NM_001754.4. PS4 is applied assuming that the variants in the Simon et al1 study are germline variants. Germline status should be confirmed in DNA derived from cultured skin fibroblasts, cultured bone marrow mesenchymal stromal cells, or hair roots.
—, no data; BEN, benign; cDNA, complementary DNA; FPD, familial platelet disorder; gnomAD, Genome Aggregation Database; HGVS, Human Genome Variation Society; LOF, loss of function; LPATH, likely pathogenic; MAF, minor allele frequency; NMD, non-sense–mediated decay, PATH, pathogenic, VUS, variant of unknown significance.
From the Simon et al1 study.
MM-VCEP assessment.
Patients are related.