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.166_193dup (p.Ala65fs)

CA891844470

571388 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 98ed23b5-7557-477d-af0e-20f02ed05e0e

HGVS expressions

NM_001754.5:c.166_193dup

NM_001754.5(RUNX1):c.166_193dup (p.Ala65fs)

NC_000021.9:g.34887005_34887032dup

CM000683.2:g.34887005_34887032dup

NC_000021.8:g.36259302_36259329dup

CM000683.1:g.36259302_36259329dup

NC_000021.7:g.35181172_35181199dup

NG_011402.2:g.1102684_1102711dup

ENST00000675419.1:c.166_193dup

ENST00000300305.7:c.166_193dup

ENST00000344691.8:c.85_112dup

ENST00000358356.9:c.85_112dup

ENST00000399237.6:c.130_157dup

ENST00000399240.5:c.85_112dup

ENST00000437180.5:c.166_193dup

ENST00000455571.5:c.127_154dup

ENST00000482318.5:c.59-6315_59-6288dup

NM_001001890.2:c.85_112dup

NM_001122607.1:c.85_112dup

NM_001754.4:c.166_193dup

NM_001001890.3:c.85_112dup

NM_001122607.2:c.85_112dup

Pathogenic

PM5_Supporting PVS1 PM2_Supporting PS4_Supporting

BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS1 PS2 PS3 BA1 PP4 PP1 PP3 PP2 PM3 PM1 PM4 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 c.166_193dup (p.Ala65Valfs*82) variant is a 28-bp duplication causing a frameshift 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 (gnomAD v2.1.1 and v3) 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 in FPD/AML patients in the literature to the best of our knowledge; however one patient meeting RUNX1-phenotype criteria is reported from a clinical laboratory (PS4_Supporting; SCV000820350.2). 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, PS4_Supporting, PM5_supporting.

PM5_Supporting

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

PVS1

The c.166_193dup (p.Ala65Valfs*82) variant is a 28-bp duplication causing a frameshift that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay.

PM2_Supporting

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

PS4_Supporting

The variant has not been reported in the literature to the best of our knowledge. Internal laboratory data reports 1 patient meeting RUNX1-phenotype criteria.

BS2

MM-VCEP deemed N/A for RUNX1

BS4

No data currently available

BS3

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.

BP2

No evidence

BP3

MM-VCEP deemed N/A for RUNX1

BP4

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

BP1

MM-VCEP deemed N/A for RUNX1

BP5

MM-VCEP deemed N/A for RUNX1

BP7

This variant is not a synonymous or intronic variant.

PS1

This variant is not a missense, or synonymous variant.

PS2

No data currently available

PS3

No data currently available

BA1

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

PP4

MM-VCEP deemed N/A for RUNX1

PP1

No data currently available

PP3

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

PP2

MM-VCEP deemed N/A for RUNX1

PM3

MM-VCEP deemed N/A for RUNX1

PM1

This variant is not a missense variant.

PM4

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

PM6

No data currently available

Approved on: 2024-03-26

Published on: 2024-03-26

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