Table 2.

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.

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