Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001754.4(RUNX1):c.1163C>A (p.Ser388Ter)

CA410147908

561222 (ClinVar)

Gene: RUNX1 (HGNC:861)

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome (MONDO:0011071)

Inheritance Mode: Autosomal dominant inheritance

UUID: 37cf5142-fd3f-4896-9da9-ca4c54b542ea

Approved on: 2024-09-10

Published on: 2024-09-10

HGVS expressions

NM_001754.4:c.1163C>A

NM_001754.4(RUNX1):c.1163C>A (p.Ser388Ter)

NC_000021.9:g.34792415G>T

CM000683.2:g.34792415G>T

NC_000021.8:g.36164712G>T

CM000683.1:g.36164712G>T

NC_000021.7:g.35086582G>T

NG_011402.2:g.1197297C>A

ENST00000675419.1:c.1163C>A

ENST00000300305.7:c.1163C>A

ENST00000344691.8:c.1082C>A

ENST00000399240.5:c.890C>A

ENST00000437180.5:c.1163C>A

ENST00000482318.5:c.*753C>A

NM_001001890.2:c.1082C>A

NM_001001890.3:c.1082C>A

NM_001754.5:c.1163C>A

Likely Pathogenic

PS3_Supporting PM2_Supporting PS4_Supporting PVS1_Strong

BA1 BS2 BS1 BS4 BS3 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS1 PP4 PP1 PP3 PP2 PM3 PM5 PM1 PM4 PM6

Evidence Links 1

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The NM_001754.4:c.1163C>A (p.Ser388Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). Transactivation assays demonstrate enhanced transactivation (>115% of wt) (PS3_Supporting; PMID: 20846103). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 20846103). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS3_Supporting, PS4_Supporting.

PS3_Supporting

Transactivation assay demonstrating moderately altered transactivation (>115% of WT).

Functional activity of our RUNX1 mutant was tested using a luciferase assay [Figure 1(D)]. The mutant demonstrated a significant increase in trans- activation when compared to wild-type RUNX1. PubMed:20846103

PM2_Supporting

The variant is absent from all population databases.

PS4_Supporting

One affected proband from PMID: 20846103.

1 affected proband with MDS and her mother has AML. PubMed:20846103

PVS1_Strong

Nonsense variant after the c.916 cutoff that do not predict to undergo NMD. But the truncated region of RUNX1 is critical to protein function.

BA1