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]

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CA410202496

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 2c4979d8-747f-4e35-9cb5-03d39c030888

Approved on: 2024-08-01

Published on: 2024-08-01

HGVS expressions

NM_001754.5:c.493G>C

NC_000021.9:g.34880572C>G

CM000683.2:g.34880572C>G

NC_000021.8:g.36252869C>G

CM000683.1:g.36252869C>G

NC_000021.7:g.35174739C>G

NG_011402.2:g.1109140G>C

ENST00000675419.1:c.493G>C

ENST00000300305.7:c.493G>C

ENST00000344691.8:c.412G>C

ENST00000358356.9:c.412G>C

ENST00000399237.6:c.457G>C

ENST00000399240.5:c.412G>C

ENST00000437180.5:c.493G>C

ENST00000482318.5:c.*83G>C

NM_001001890.2:c.412G>C

NM_001122607.1:c.412G>C

NM_001754.4:c.493G>C

NM_001001890.3:c.412G>C

NM_001122607.2:c.412G>C

Uncertain Significance

PM2_Supporting PM1_Supporting PP3 PS4_Supporting

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

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.493G>C (p.Gly165Arg) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a REVEL score greater than 0.88 (0.952) and a SpliceAI score less than 0.20 (0.01, 8bp, Donor Loss) (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant has been reported in one proband meeting at least one of the RUNX1 phenotypic criteria (PS4_supporting; PMID: 29797310, Table 2). 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: PM2_supporting, PP3, PM1_supporting, PS4_supporting.

PM2_Supporting

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).

PM1_Supporting

This variant affects one of the other residues (AA 89-204) within the RHD (PM1_supporting)

PP3

This variant has a REVEL score greater than 0.88 (0.952) and SpliceAI score less than 0.20 (0.01 , 8bp, Donor Loss) (PP3)

PS4_Supporting

This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 29797310, Table 2).

BP5

This rule is not applicable for MM-VCEP

BP7

Not a silent or intronic variant

BP2

Variant not present in gnomAD

BP4

PP3 met

BP1

This rule is not applicable for MM-VCEP

BP3

This rule is not applicable for MM-VCEP

PS2

No case studies found that would confirm de novo

PS3

No functional data found

PS1

Amino Acid location has not previously been determined to be pathogenic

PVS1

Not a null variant

PP1

No case studies found with segregation

PP4

This rule is not applicable for MM-VCEP

PP2

This rule is not applicable for MM-VCEP

PM6

No case studies found that would confirm de novo

PM3

This rule is not applicable for MM-VCEP

PM5

PM5 is not applicable because variant meets PM1

PM4

Not an indel variant

BA1

Meets PM2_supporting

BS4

No case studies found with segregation

BS3

No functional data found

BS1

Meets PM2_supporting

BS2

This rule is not applicable for MM-VCEP

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