Variant: NM_001754.5(RUNX1):c.159del (p.Ser53fs)

CA658824424

561228 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: c87368df-0745-4c45-8410-66cf1bc6fd75

Approved on: 2024-03-26

Published on: 2024-03-26

HGVS expressions

NM_001754.5:c.159del
NM_001754.5(RUNX1):c.159del (p.Ser53fs)
NC_000021.9:g.34887035del
CM000683.2:g.34887035del
NC_000021.8:g.36259332del
CM000683.1:g.36259332del
NC_000021.7:g.35181202del
NG_011402.2:g.1102677del
ENST00000675419.1:c.159del
ENST00000300305.7:c.159del
ENST00000344691.8:c.78del
ENST00000358356.9:c.78del
ENST00000399237.6:c.123del
ENST00000399240.5:c.78del
ENST00000437180.5:c.159del
ENST00000455571.5:c.120del
ENST00000482318.5:c.59-6322del
NM_001001890.2:c.78del
NM_001122607.1:c.78del
NM_001754.4:c.159del
NM_001001890.3:c.78del
NM_001122607.2:c.78del

Pathogenic

• Met criteria codes: PVS1 PM5_Supporting PM2_Supporting

• Not Met criteria codes: BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS4 PS3 PS1 PM3 PM1 PM4 PM6 BA1 PP4 PP1 PP3 PP2 BS2 BS4 BS3 BS1

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 NM_001754.4(RUNX1):c.159del (p.Ser53fs) 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 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.

Met criteria codes

• PVS1: The 1-bp deletion causes a frameshift and results in premature termination of translation. The resulting transcript is expected to undergo NMD.
• 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).

Not Met criteria codes

• BP2: No data currently available
• 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.
• PS2: No data currently available
• PS4: The variant has not been reported in patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. From internal laboratory data (SCV000807764.1): Patients do not meet RUNX1 phenotype criteria.
• PS3: In vitro or in vivo functional data has not been reported for this variant in the literature.
• PS1: This variant is not a missense, or synonymous variant.
• PM3: This rule is not applicable for MM-VCEP.
• PM1: This variant is not a missense variant.
• PM4: This variant is not an in-frame deletion/insertion.
• PM6: No data currently available
• BA1: This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
• PP4: This rule is not applicable for MM-VCEP.
• PP1: No data currently available
• PP3: This variant does not have applicable in-silico data available.
• PP2: This rule is not applicable for MM-VCEP.
• BS2: This rule is not applicable for MM-VCEP.
• BS4: No data currently available
• 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.