Variant: NM_001754.5(RUNX1):c.965del (p.Leu321_Ser322insTer)

Version: 1.0
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CA2573157369

1460663 (ClinVar)

Gene: RUNX1 (HGNC:861)

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: ebe7d39f-0b88-4af9-a8d3-5c53ab3d0a9a

Approved on: 2024-09-10

Published on: 2024-09-10

HGVS expressions

NM_001754.5:c.965del
NM_001754.5(RUNX1):c.965del (p.Leu321_Ser322insTer)
NC_000021.9:g.34799303del
CM000683.2:g.34799303del
NC_000021.8:g.36171600del
CM000683.1:g.36171600del
NC_000021.7:g.35093470del
NG_011402.2:g.1190409del
ENST00000675419.1:c.965del
ENST00000300305.7:c.965del
ENST00000344691.8:c.884del
ENST00000399240.5:c.692del
ENST00000437180.5:c.965del
ENST00000482318.5:c.*555del
NM_001001890.2:c.884del
NM_001754.4:c.965del
NM_001001890.3:c.884del

Likely Pathogenic

• Met criteria codes: PM2_Supporting PM5_Supporting PVS1_Strong

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

NM_001754.5(RUNX1):c.965del (p.Ser322Ter) is a nonsense variant located downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). It is not expected to undergo nonsense-mediated decay, and the resulting frameshift affects positions c.759-c.1440 as per VCEP specifications, which are critical for protein function (PVS1_Strong). 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 likely pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v.3.1.2 and gnomAD v2.1.1 which have at least 20x coverage for RUNX1 (PM2_supporting).
• PM5_Supporting: This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting).
• PVS1_Strong: This variant is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (nonsense c.917-c.1440 as per VCEP specifications) (PVS1_Strong).

Not Met criteria codes

• BP7: This variant is not a synonymous or intronic variant.
• BP5: This rule is not applicable for the MM.VCEP.
• 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 the MM.VCEP.
• BP4: This variant does not have applicable in-silico data available.
• BP1: This rule is not applicable for the MM.VCEP.
• BS4: Segregation data for this variant has not been reported in literature.
• BS3: In vitro or in vivo functional data has not been reported for this variant in the literature.
• BS1: This variant is absent from gnomAD v.3.1.2 and gnomAD v2.1.1 which have at least 20x coverage for RUNX1 (PM2_supporting).
• BS2: This rule is not applicable for the MM.VCEP.
• PP1: Segregation data for this variant has not been reported in literature.
• PP4: This rule is not applicable for the MM.VCEP.
• PP3: This variant does not have applicable in-silico data available.
• PP2: This rule is not applicable for the MM.VCEP.
• PS2: De novo data for this variant has not been reported in literature.
• PS3: In vitro or in vivo functional data has not been reported for this variant in the literature.
• PS1: There has not yet been a missense change determined to be pathogenic at this amino acid residue.
• BA1: This variant is absent from gnomAD v.3.1.2 and gnomAD v2.1.1 which have at least 20x coverage for RUNX1 (PM2_supporting).
• PM6: De novo data for this variant has not been reported in literature.
• PM1: This variant does not affect any of the following amino acid residues, nor is it located within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 OR within residues 89-204.
• PM3: This rule is not applicable for the MM.VCEP.
• PM4: This variant is not an in-frame deletion/insertion.