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]

Link to SEPIO compliant JSON-LD document

CA410202636

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ebf65895-fcd2-4118-84d5-2072b4b4812f

Approved on: 2024-07-11

Published on: 2024-07-11

HGVS expressions

NM_001754.5:c.425C>A

NC_000021.9:g.34880640G>T

CM000683.2:g.34880640G>T

NC_000021.8:g.36252937G>T

CM000683.1:g.36252937G>T

NC_000021.7:g.35174807G>T

NG_011402.2:g.1109072C>A

ENST00000675419.1:c.425C>A

ENST00000300305.7:c.425C>A

ENST00000344691.8:c.344C>A

ENST00000358356.9:c.344C>A

ENST00000399237.6:c.389C>A

ENST00000399240.5:c.344C>A

ENST00000437180.5:c.425C>A

ENST00000455571.5:c.386C>A

ENST00000482318.5:c.*15C>A

NM_001001890.2:c.344C>A

NM_001122607.1:c.344C>A

NM_001754.4:c.425C>A

NM_001001890.3:c.344C>A

NM_001122607.2:c.344C>A

Uncertain Significance

PM1_Supporting PM2_Supporting PP3 PS4_Supporting

PVS1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PM6 PM3 PM5 PM4 PS2 PS1 PS3 PP1 PP4 PP2 BA1

Evidence Links 0

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

NM_001754.5(RUNX1):c.425C>A (p.Ala142Asp) is a missense variant which has a REVEL score ≥ 0.88 (0.919) (PP3). This variant is found within the Runt Homology Domain, but does not occur at a known hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; PMID: 29146900). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting, PS4_supporting.

PM1_Supporting

This variant affects one of the other residues (AA 89-204) within the RHD (PM1_Supporting).

PM2_Supporting

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).

PP3

This missense variant has a REVEL score ≥ 0.88 (0.919) (PP3).

PS4_Supporting

This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 29146900).

PVS1

This variant is not a null variant.

BS2

This rule is not applicable for MM-VCEP.

BS4

Segregation data for this variant has not been reported in literature.

BS3

In vitro or in vivo functional data has not been reported for this variant in the literature.

BS1

This variant does not have a MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental dataset.

BP5

This rule is not applicable for MM-VCEP.

BP7

This variant is not a synonymous or intronic variant.

BP2

This variant has not been observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.

BP3

This rule is not applicable for MM-VCEP.

BP4

This missense variant does not have a REVEL score < 0.50.

BP1

This rule is not applicable for MM-VCEP.

PM6

De novo data for this variant has not been reported in literature.

PM3

This rule is not applicable for MM-VCEP.

PM5

There has not yet been a different missense change determined to be pathogenic at this amino acid residue.

PM4

This variant is not an in-frame deletion/insertion.

PS2

De novo data for this variant has not been reported in literature.

PS1

There has not yet been a missense change determined to be pathogenic at this amino acid residue.

PS3

In vitro or in vivo functional data has not been reported for this variant in the literature.

PP1

Segregation data for this variant has not been reported in literature.

PP4

This rule is not applicable for MM-VCEP.

PP2

This rule is not applicable for MM-VCEP.

BA1

This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.

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