Variant: NM_001754.5(RUNX1):c.352-1G>A

CA410202793

436616 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: bacb4dd5-65e9-43dd-9c45-b3d9b6a59f6d

Approved on: 2024-03-26

Published on: 2024-03-26

HGVS expressions

NM_001754.5:c.352-1G>A
NM_001754.5(RUNX1):c.352-1G>A
NC_000021.9:g.34880714C>T
CM000683.2:g.34880714C>T
NC_000021.8:g.36253011C>T
CM000683.1:g.36253011C>T
NC_000021.7:g.35174881C>T
NG_011402.2:g.1108998G>A
ENST00000675419.1:c.352-1G>A
ENST00000300305.7:c.352-1G>A
ENST00000344691.8:c.271-1G>A
ENST00000358356.9:c.271-1G>A
ENST00000399237.6:c.316-1G>A
ENST00000399240.5:c.271-1G>A
ENST00000437180.5:c.352-1G>A
ENST00000455571.5:c.313-1G>A
ENST00000482318.5:c.59-1G>A
NM_001001890.2:c.271-1G>A
NM_001122607.1:c.271-1G>A
NM_001754.4:c.352-1G>A
NM_001001890.3:c.271-1G>A
NM_001122607.2:c.271-1G>A

Pathogenic

• Met criteria codes: PP1 PM2_Supporting PS4_Supporting PVS1

• Not Met criteria codes: BP5 BP7 BP4 BP3 BP1 BP2 PS1 PS2 PS3 BA1 PP2 PP3 PP4 PM6 PM1 PM3 PM5 PM4 BS1 BS4 BS3 BS2

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:c.352-1G>A variant is a canonical splice site variant that is predicted to introduce a frameshift and 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 has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 26175287). This variant was found to co-segregate with disease in multiple affected family members, with three meioses observed in one family (PP1; PMID: 26175287). 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, PP1.

Met criteria codes

• PP1: 4 affected individuals (3 meioses) in one family with FPD/AML (Pedigree 4).
• PM2_Supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).
• PS4_Supporting: 1 affected proband in a family with FPD/AML.
• PVS1: A variant at canonical splice site (-1). The transcription predicts to skip exon 5 and generates a frameshift (-1) that predicts to undergo NMD.

Not Met criteria codes

• BP5: This rule is not applicable for MM-VCEP.
• BP7: This variant is a splicing variant at a canonical splice site.
• BP4: This variant does not have applicable in-silico data available.
• BP3: This rule is not applicable for MM-VCEP.
• BP1: This rule is not applicable for 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.
• PS1: This variant is not a missense, or synonymous variant.
• 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.
• BA1: This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
• PP2: This rule is not applicable for MM-VCEP.
• PP3: This variant does not have applicable in-silico data available.
• PP4: This rule is not applicable for MM-VCEP.
• PM6: De novo data for this variant has not been reported in literature.
• PM1: This variant is not a missense variant.
• PM3: This rule is not applicable for MM-VCEP.
• PM5: This variant is not a missense, or synonymous variant.
• PM4: This variant is not an in-frame deletion/insertion.
• BS1: This variant does not have a MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental dataset.
• BS4: Segregation was not found to be absent in two or more informative meiosis.
• BS3: In vitro or in vivo functional data has not been reported for this variant in the literature.
• BS2: This rule is not applicable for MM-VCEP.