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.165dup (p.Leu56fs)

CA2387297219

1013619 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 75278995-1bc4-47dc-a356-e9f245681205

HGVS expressions

NM_001754.5:c.164_165insG

NM_001754.5:c.165dup

NM_001754.5(RUNX1):c.165dup (p.Leu56fs)

NC_000021.9:g.34887029dup

CM000683.2:g.34887029dup

NC_000021.8:g.36259326dup

CM000683.1:g.36259326dup

NC_000021.7:g.35181196dup

NG_011402.2:g.1102683dup

ENST00000675419.1:c.165dup

ENST00000300305.7:c.165dup

ENST00000344691.8:c.84dup

ENST00000358356.9:c.84dup

ENST00000399237.6:c.129dup

ENST00000399240.5:c.84dup

ENST00000437180.5:c.165dup

ENST00000455571.5:c.126dup

ENST00000482318.5:c.59-6316dup

NM_001001890.2:c.84dup

NM_001122607.1:c.84dup

NM_001754.4:c.165dup

NM_001001890.3:c.84dup

NM_001122607.2:c.84dup

Pathogenic

PM2_Supporting PVS1 PM5_Supporting PS4_Supporting

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

NM_001754.5(RUNX1):c.165dup (p.Leu56ValfsTer?) is a duplication frameshift variant which results in a termination sequence 82 residues later. This variant is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98-c.779 as per VCEP specifications) (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). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 18723428). 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, PM5_supporting, PM2_supporting, PS4_supporting.

PM2_Supporting

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

PVS1

This variant is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98-c.779 as per VCEP specifications) (PVS1).

PM5_Supporting

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

PS4_Supporting

This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 18723428).

BA1

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

BS4

Segregation was not found to be absent in two or more informative meiosis.

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.

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

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.

PS2

This variant does not have a proven de novo occurrence in the literature.

PS3

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

PS1

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

PP1

This variant was not found to co-segregate with disease in 3 or more affected family members in the literature.

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

PM1

This variant does not affect any of the following amino acid residues, nor is it located within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 OR within residues 89-204.

PM4

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

PM3

This rule is not applicable for MM-VCEP

PM6

This variant does not have two or more assumed de novo occurrences in the literature.

Approved on: 2024-03-26

Published on: 2024-03-26

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