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

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

Approved on: 2024-03-26

Published on: 2024-03-26

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

• Met criteria codes: PM5_Supporting PM2_Supporting PVS1 PS4_Supporting

• Not Met criteria codes: BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS1 PS2 PS3 PP4 PP1 PP3 PP2 BA1 PM3 PM1 PM4 PM6

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

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.

Met criteria codes

• PM5_Supporting: This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting).
• PM2_Supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_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.
• 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.

Not Met criteria codes

• 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.
• BP5: MM-VCEP deemed N/A for RUNX1
• BP7: This variant is not a synonymous or intronic variant.
• 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
• PS1: This variant is not a missense, or synonymous variant.
• PS2: No data currently available
• PS3: No data currently available
• 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
• BA1: This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
• 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