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.424dup (p.Ala142fs)

CA658824419

561238 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 9a538152-2ada-41e8-9f16-2172b1c46648

HGVS expressions

NM_001754.5:c.424dup

NM_001754.5(RUNX1):c.424dup (p.Ala142fs)

NC_000021.9:g.34880642dup

CM000683.2:g.34880642dup

NC_000021.8:g.36252939dup

CM000683.1:g.36252939dup

NC_000021.7:g.35174809dup

NG_011402.2:g.1109071dup

ENST00000675419.1:c.424dup

ENST00000300305.7:c.424dup

ENST00000344691.8:c.343dup

ENST00000358356.9:c.343dup

ENST00000399237.6:c.388dup

ENST00000399240.5:c.343dup

ENST00000437180.5:c.424dup

ENST00000455571.5:c.385dup

ENST00000482318.5:c.*14dup

NM_001001890.2:c.343dup

NM_001122607.1:c.343dup

NM_001754.4:c.424dup

NM_001001890.3:c.343dup

NM_001122607.2:c.343dup

Pathogenic

PM2_Supporting PVS1 PM5_Supporting

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

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

The NM_001754.4:c.424dup (p.Ala142fs) variant is a frameshift 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). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). The variant has not been reported as germ-line in patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. 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, PM2_supporting, PM5_supporting.

PM2_Supporting

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

PVS1

The variant causes a frameshift and early termination of translation. The resulting transcript is predicted to undergo NMD.

PM5_Supporting

This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting).

BA1

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

BS3

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

BS4

No data currently available

BS1

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

BS2

This rule is not applicable for MM-VCEP.

BP7

This variant is not a synonymous or intronic variant.

BP5

This rule is not applicable for MM-VCEP.

BP3

This rule is not applicable for MM-VCEP.

BP4

This variant does not have applicable in-silico data available.

BP1

This rule is not applicable for MM-VCEP.

BP2

No data currently available

PS1

This variant is not a missense, or synonymous variant.

PS3

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

PS2

No data currently available

PS4

The variant has not been reported germ line in patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. PMID: 28933735 reports a patient with AML in whom the variant is somatic - not counted towards PS4. From internal laboratory data (SCV000807781.1): In the absence of phenotype information on the individual, they were not included in PS4 scoring.

PP3

This variant does not have applicable in-silico data available.

PP2

This rule is not applicable for MM-VCEP.

PP4

This rule is not applicable for MM-VCEP.

PP1

No data currently available

PM4

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

PM3

This rule is not applicable for MM-VCEP.

PM1

This variant is not a missense variant.

PM6

No data currently available

Approved on: 2024-03-26

Published on: 2024-03-26

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