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.504_508dup (p.Gly170fs)

CA658824417

561244 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1301eed8-2379-4369-b9ec-14256ec24807

HGVS expressions

NM_001754.5:c.504_508dup

NM_001754.5(RUNX1):c.504_508dup (p.Gly170fs)

NC_000021.9:g.34880558_34880562dup

CM000683.2:g.34880558_34880562dup

NC_000021.8:g.36252855_36252859dup

CM000683.1:g.36252855_36252859dup

NC_000021.7:g.35174725_35174729dup

NG_011402.2:g.1109151_1109155dup

ENST00000675419.1:c.504_508dup

ENST00000300305.7:c.504_508dup

ENST00000344691.8:c.423_427dup

ENST00000358356.9:c.423_427dup

ENST00000399237.6:c.468_472dup

ENST00000399240.5:c.423_427dup

ENST00000437180.5:c.504_508dup

ENST00000482318.5:c.*94_*98dup

NM_001001890.2:c.423_427dup

NM_001122607.1:c.423_427dup

NM_001754.4:c.504_508dup

NM_001001890.3:c.423_427dup

NM_001122607.2:c.423_427dup

Pathogenic

PM5_Supporting PVS1 PM2_Supporting

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

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

This frameshift duplication, located in a critical protein domain of an exon present in all biologically-relevant transcripts, is predicted to undergo NMD (PVS1). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). 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.

PM5_Supporting

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

PVS1

Frameshift variant predicted to undergo NMD, exon is present in all biologically-relevant transcripts, and the location of the variant is within a known critical protein domain.

PM2_Supporting

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

PS4

One patient with AML was found to have G170Efs, but it is unclear if this variant is of germline origin and if it is the same alteration as c.504_508dup (PMID: 31367767). Note that Prevention Genetics reviewed this variant due to their Variant Interpretation Service, but the laboratory has not identified this variant in a patient, per Michael Chicka, PhD.

PS2

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

PS3

This variant has not been functionally evaluated, but JAX-CKB (https://ckb.jax.org/geneVariant/show?geneVariantId=22040) predicted that this is a LOF variant based on functional data of other variants in which the runt homology domain and transactivation domain are disrupted/lost (PMID: 25840971).

PS1

This variant is not a missense, or synonymous variant.

PP4

This rule is not applicable for MM-VCEP.

PP1

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

PP3

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

PP2

This rule is not applicable for MM-VCEP.

PM3

This rule is not applicable for MM-VCEP.

PM1

Overlaps with hotspot/critical regions, but is not applied for variants that meet PVS1 which already incorporates the region.

PM4

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

PM6

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

BA1

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

BS2

Not applicable

BS4

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

BS3

This variant has not been featured in in vitro or in vivo functional studies that show no damaging effect on protein function or splicing.

BS1

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

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 variant does not have applicable in-silico data available.

BP1

This rule is not applicable for MM-VCEP.

BP5

This rule is not applicable for MM-VCEP.

BP7

This variant is not a synonymous or intronic variant.

Approved on: 2024-03-26

Published on: 2024-03-26

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