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

Variant: NM_001754.5(RUNX1):c.292del (p.Leu98fs)

CA512318852

561231 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: bf3e82b4-cd47-4a45-bab9-d08dd560bc37

HGVS expressions

NM_001754.5:c.292del

NM_001754.5(RUNX1):c.292del (p.Leu98fs)

NC_000021.9:g.34886903del

CM000683.2:g.34886903del

NC_000021.8:g.36259200del

CM000683.1:g.36259200del

NC_000021.7:g.35181070del

NG_011402.2:g.1102810del

ENST00000675419.1:c.292del

ENST00000300305.7:c.292del

ENST00000344691.8:c.211del

ENST00000358356.9:c.211del

ENST00000399237.6:c.256del

ENST00000399240.5:c.211del

ENST00000437180.5:c.292del

ENST00000455571.5:c.253del

ENST00000482318.5:c.59-6189del

NM_001001890.2:c.211del

NM_001122607.1:c.211del

NM_001754.4:c.292del

NM_001001890.3:c.211del

NM_001122607.2:c.211del

Pathogenic

PM2_Supporting PM5_Supporting PVS1

PM6 PM3 PM1 PM4 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS4 PS3 PS1 BA1 PP4 PP1 PP3 PP2

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The NM_001754.5:c.292del p.(Leu98SerfsTer24) variant is a frameshift variant that is predicted to introduce a premature stop codon and is expected to result in nonsense-mediated mRNA decay. All the biologically relevant transcripts are predicted to be affected (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting), and is a nonsense variant downstream of c.98 (in transcript NM_001754.4) (PM5_supporting). The c.292del variant has been reported in one proband with a diagnosis of clonal cytopenia of undetermined significance (PMID: 33179473). This variant was identified by NGS and had a VAF of 33%. However, its germline origin was not assessed in the study. Therefore, we cannot assess case-study/segregation criteria. In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting.

PM2_Supporting

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

PM5_Supporting

This is a nonsense/frameshift variants downstream of c.98 (in transcript NM_001754.4).

PVS1

PM6

This rule is not applicable to this variant since there is no reported evidence.

PM3

The MMVCEP does not evaluate this rule.

PM1

This variant is a deletion

PM4

This rule is not applicable to the variant since it is a frameshift deletion.

BS2

The MMVCEP does not evaluate this rule.

BS4

This rule is not applicable to this variant since there is not informative meiosis.

BS3

This rule is not applicable to the variant since no functional studies have been found.

BS1

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

BP2

This rule is not applicable to this variant since there is no reported evidence.

BP3

This rule is not applicable to the variant since it is a frameshift deletion.

BP4

This rule is not applicable to the variant since it is a deletion.

BP1

The MMVCEP does not evaluate this rule and the variant is a deletion.

BP5

The MMVCEP does not evaluate this rule.

BP7

This rule is not applicable to the variant since it is a deletion.

PS2

This rule is not applicable to this variant since there is no reported evidence.

PS4

The c.292del variant has been reported in one proband with a diagnosis of clonal cytopenia of undetermined significance (PMID: 33179473). This variant was identified by NGS and had a VAF of 33%. However, its germline origin was not assessed in the study.

PS3

This rule is not applicable to the variant since no functional studies have been found.

PS1

This rule is not applicable to the variant since it is a deletion.

BA1

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

PP4

The MMVCEP does not evaluate this rule.

PP1

This rule is not applicable to this variant since there is not informative meiosis.

PP3

This rule is not applicable to the variant since it is a deletion.

PP2

This rule is not applicable to the variant since it is a deletion.

Approved on: 2023-12-09

Published on: 2023-12-09

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