Variant: NM_001754.5(RUNX1):c.1242C>G (p.Tyr414Ter)

CA410147696

1194557 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 8d6c48db-347f-47c5-bd52-608bcd6c3127

Approved on: 2025-07-11

Published on: 2025-07-11

HGVS expressions

NM_001754.5:c.1242C>G
NM_001754.5(RUNX1):c.1242C>G (p.Tyr414Ter)
NC_000021.9:g.34792336G>C
CM000683.2:g.34792336G>C
NC_000021.8:g.36164633G>C
CM000683.1:g.36164633G>C
NC_000021.7:g.35086503G>C
NG_011402.2:g.1197376C>G
ENST00000675419.1:c.1242C>G
ENST00000300305.7:c.1242C>G
ENST00000344691.8:c.1161C>G
ENST00000399240.5:c.969C>G
ENST00000437180.5:c.1242C>G
ENST00000482318.5:c.*832C>G
NM_001001890.2:c.1161C>G
NM_001754.4:c.1242C>G
NM_001001890.3:c.1161C>G

Pathogenic

• Met criteria codes: PS4 PM5_Supporting PP1 PM2_Supporting PVS1_Strong

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

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Evidence submitted by expert panel

Myeloid Malignancy VCEP

NM_001754.5(RUNX1):c.1242C>G (p.Tyr414Ter) is a nonsense variant which is not predicted to undergo nonsense-mediated decay, and the truncated/altered region is critical for protein function (nonsense c.917-c.1440 as per VCEP specifications) (PVS1_Strong, PM5_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has been reported in four probands meeting at least one of the RUNX1-phenotypic criteria (PMID: 33560381, 37680325, 37458302, 37738626) (PS4). It was also found to co-segregate with disease in multiple affected family members, with three meioses observed across two families (PP1; PMID: 37680325, 37458302). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM5_supporting, PM2_supporting, PP1, PS4.

Met criteria codes

• PS4: This variant has been reported in four probands meeting at least one of the RUNX1-phenotypic criteria (PMID: 33560381, 37680325, 37458302, 37738626) (PS4).
• PM5_Supporting: This variant is a nonsense variant that is downstream of c.98 (PM5_Supporting).
• PP1: This variant was found to co-segregate with disease in multiple affected family members, with three meioses observed across two families (PP1; PMID: 37680325, 37458302).
• PM2_Supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).
• PVS1_Strong: This variant is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (nonsense c.917-c.1440 as per VCEP specifications) (PVS1_Strong).

Not Met criteria codes

• PS2: No case studies found
• PS3: No functional studies found
• PS1: Amino acid change has not been previously established as a pathogenic variant.
• PP4: This rule is not applicable for the MMVCEP
• PP3: Not a missense variant or synonymous/ intronic variant
• PP2: This rule is not applicable for the MMVCEP
• PM1: Variant not within the RHD or defined hotspots
• PM3: This rule is not applicable for the MMVCEP
• PM4: Not an in frame deletion/insertion.
• PM6: No case studies found
• BA1: The variant is absent in gnomAD v2.1.1 and v3.1.2.
• BS2: This rule is not applicable for the MMVCEP
• BS4: No case studies found
• BS3: No functional studies found
• BS1: The variant is absent in gnomAD v2.1.1 and v3.1.2.
• BP7: Not a synonymous/intronic variant.
• BP5: This rule is not applicable for the MMVCEP
• BP2: No homozygotes present in gnomAD v2.1.1. and v3.1.2.
• BP3: This rule is not applicable for the MMVCEP.
• BP4: Not a missense variant or synonymous/ intronic variant
• BP1: This rule is not applicable for the MMVCEP