Variant: NM_001754.4(RUNX1):c.352-1G>A

CA410202793

436616 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

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

Approved on: 2019-08-01

Published on: 2019-08-02

HGVS expressions

NM_001754.4:c.352-1G>A
NM_001754.4(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_001001890.3:c.271-1G>A
NM_001122607.2:c.271-1G>A
NM_001754.5:c.352-1G>A

Pathogenic

• Met criteria codes: PS4_Supporting PVS1 PP1 PM2

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

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

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). 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, PS4_Supporting, PP1.

Met criteria codes

• 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.
• PP1: 4 affected individuals (3 meioses) in one family with FPD/AML (Pedigree 4).
• PM2: The variant is absent from all population databases.

Not Met criteria codes

• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline