Variant: NM_001754.5(RUNX1):c.1219_1221delinsGGGATCGTTCGGA (p.Tyr407fs)

CA2499225871

1065583 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 04603405-3e02-4884-8398-0105856dc8d2

Approved on: 2023-12-09

Published on: 2023-12-09

HGVS expressions

NM_001754.5:c.1219_1221delinsGGGATCGTTCGGA
NM_001754.5:c.1219_1221delTACinsGGGATCGTTCGGA
NM_001754.5(RUNX1):c.1219_1221delinsGGGATCGTTCGGA (p.Tyr407fs)
NC_000021.9:g.34792357_34792359delinsTCCGAACGATCCC
CM000683.2:g.34792357_34792359delinsTCCGAACGATCCC
NC_000021.8:g.36164654_36164656delinsTCCGAACGATCCC
CM000683.1:g.36164654_36164656delinsTCCGAACGATCCC
NC_000021.7:g.35086524_35086526delinsTCCGAACGATCCC
NG_011402.2:g.1197353_1197355delinsGGGATCGTTCGGA
ENST00000675419.1:c.1219_1221delinsGGGATCGTTCGGA
ENST00000300305.7:c.1219_1221delinsGGGATCGTTCGGA
ENST00000344691.8:c.1138_1140delinsGGGATCGTTCGGA
ENST00000399240.5:c.946_948delinsGGGATCGTTCGGA
ENST00000437180.5:c.1219_1221delinsGGGATCGTTCGGA
ENST00000482318.5:c.*809_*811delinsGGGATCGTTCGGA
NM_001001890.2:c.1138_1140delinsGGGATCGTTCGGA
NM_001754.4:c.1219_1221delinsGGGATCGTTCGGA
NM_001001890.3:c.1138_1140delinsGGGATCGTTCGGA

Likely Pathogenic

• Met criteria codes: PM5_Supporting PM2_Supporting PVS1_Strong

• Not Met criteria codes: PM6 PM1 PM3 PM4 BA1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS4 PS2 PS3 PS1 PP1 PP4 PP3 PP2

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The c.1219_1221delinsGGGATCGTTCGGA (p.Tyr407Glyfs*196) (NM_001754.5) variant in RUNX1 - whose mechanism of disease is established to be loss-of-function - is a protein extension variant that is predicted to escape nonsense-mediated decay but alters a region critical to protein function (transactivation domain, inhibitory domain, and/or the VWRPY motif) (PVS1_Strong). This variant is absent from gnomAD v2, v3, and v4 with at least 20 coverage (PM2_Supporting). Only the somatic variant has been reported in a patient with mixed phenotype acute leukemia (ClinVar SCV001573164.1), but it is of note that other pathogenic/likely pathogenic frameshift alterations in exon 8 have been reported (PMID: 35764482), and other C-terminal frameshift variants have shown loss of transactivation ability and a dominant-negative effect (PMID: 14615365, 19808697, 25840971) (PM5_Supporting). In summary, this variant meets the criteria to be classified as 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)

Met criteria codes

• PM5_Supporting: Other pathogenic or likely pathogenic frameshift alterations in exon 8 have been reported (Feurstein et al., 2022, 35764482 - Supplementary Table 5).
• PM2_Supporting: Completely absent from gnomAD v2+v3+v4 with a mean coverage of at least 20X.
• PVS1_Strong: Fig. 2 in PMID: 31648317

Not Met criteria codes

• PM6: No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: Not applicable
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: Completely absent from gnomAD v2+v3+v4 with a mean coverage of at least 20X.
• BS2: Not applicable
• BS4: No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
• BS3: No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
• BS1: Completely absent from gnomAD v2+v3+v4 with a mean coverage of at least 20X.
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: Not applicable
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: Not applicable
• BP5: Not applicable
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: The variant was confirmed somatically in a patient with mixed phenotype acute leukemia (ClinVar SCV001573164.1). No additional cases were found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
• PS2: No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
• PS3: No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
• PP4: Not applicable
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: Not applicable