Variant: NM_001754.5:c.968del

CA2573320718

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: df9db754-0c0d-421c-b101-7a89b3756f07

Approved on: 2023-12-09

Published on: 2023-12-09

HGVS expressions

NM_001754.5:c.968del
NC_000021.9:g.34792610del
CM000683.2:g.34792610del
NC_000021.8:g.36164907del
CM000683.1:g.36164907del
NC_000021.7:g.35086777del
NG_011402.2:g.1197102del
ENST00000675419.1:c.968del
ENST00000300305.7:c.968del
ENST00000344691.8:c.887del
ENST00000399240.5:c.695del
ENST00000437180.5:c.968del
ENST00000482318.5:c.*558del
NM_001001890.2:c.887del
NM_001754.4:c.968del
NM_001001890.3:c.887del

Likely Pathogenic

• Met criteria codes: PS2_Supporting PS4_Supporting PM2_Supporting PVS1_Strong

• Not Met criteria codes: BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS1 PS3 BA1 PP4 PP1 PP3 PP2 PM6 PM5 PM3 PM1 PM4

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_001754.5:c.968del (p.Thr323ArgfsTer5) variant in RUNX1 is a frameshift variant that is not expected to result in nonsense-mediated mRNA decay, but the predicted truncated/altered region is critical for protein function (PVS1_strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant was identified in a patient meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; internal data). The de novo status has been confirmed (PS2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PS2_supporting, PS4_supporting.

Met criteria codes

• PS2_Supporting: De novo status has been confirmed.
• PS4_Supporting: One proband meeting at least one RUNX1-phenotypic criteria (AML).
• PM2_Supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting).
• PVS1_Strong: Frameshift variant in between c.759 and c.1440. This region is critical to protein function. This change is not predicted to undergo NMD.

Not Met criteria codes

• BS2: This rule is not applicable to the MMVCEP.
• BS4: The patient with the AML is the only one that carry the variant in the family.
• BS3: No data available.
• BS1: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2.
• BP2: No data available.
• BP3: This is a frameshift variant.
• BP4: This is a frameshift variant.
• BP1: This rule is not applicable to the MMVCEP.
• BP5: This rule is not applicable to the MMVCEP.
• BP7: This is a frameshift variant.
• PS1: There is no previous AA change reviewed by the expert panel at this location.
• PS3: No data available.
• BA1: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2.
• PP4: This rule is not applicable to the MMVCEP.
• PP1: No data available.
• PP3: This is a frameshift variant.
• PP2: This rule is not applicable to the MMVCEP.
• PM6: de novo status was confirmed.
• PM5: This change is a frameshift.
• PM3: Dominant inheritance mode.
• PM1: Variant not located in 89-204 AA residues.
• PM4: This is a frameshift variant.