Variant: NM_001754.4(RUNX1):c.351+1G>A

CA410203336

561236 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 603cd528-c485-4e30-934a-cabde6c6d80d

Approved on: 2021-01-11

Published on: 2021-01-11

HGVS expressions

NM_001754.4:c.351+1G>A
NM_001754.4(RUNX1):c.351+1G>A
NC_000021.9:g.34886842C>T
CM000683.2:g.34886842C>T
NC_000021.8:g.36259139C>T
CM000683.1:g.36259139C>T
NC_000021.7:g.35181009C>T
NG_011402.2:g.1102870G>A
ENST00000675419.1:c.351+1G>A
ENST00000300305.7:c.351+1G>A
ENST00000344691.8:c.270+1G>A
ENST00000358356.9:c.270+1G>A
ENST00000399237.6:c.315+1G>A
ENST00000399240.5:c.270+1G>A
ENST00000437180.5:c.351+1G>A
ENST00000455571.5:c.312+1G>A
ENST00000482318.5:c.59-6129G>A
NM_001001890.2:c.270+1G>A
NM_001122607.1:c.270+1G>A
NM_001001890.3:c.270+1G>A
NM_001122607.2:c.270+1G>A
NM_001754.5:c.351+1G>A

Pathogenic

• Met criteria codes: PVS1 PM2 PS4_Moderate

• Not Met criteria codes: BS2 BS1 BS4 BS3 PS1 PS2 PS3 BP4 BP3 BP1 BP2 BP5 BP7 BA1 PP1 PP2 PP3 PP4 PM1 PM3 PM5 PM4 PM6

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The c.351+1G>A is a splice donor variant that is predicted to introduce exon 4 skipping and a frameshift with 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 (gnomAD v2.1.1 and v3). This variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 27931139). 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.

Met criteria codes

• PVS1: The c.351+1G>A is a splice donor variant that is predicted to introduce exon 4 skipping and a frameshift with a premature stop codon and expected to result in nonsense-mediated mRNA decay.
• PM2: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (gnomAD v2.1.1 and v3).
• PS4_Moderate: 2 probands (1 from PMID: 27931139 and 1 unpublished) meet RUNX1 phenotype criteria.

Not Met criteria codes

• BS2: MM-VCEP deemed N/A for RUNX1
• BS1: Variant meets PM2
• BS4: No evidence
• BS3: No data currently available
• PS1: N/A
• PS2: No data currently available
• PS3: No data currently available
• BP4: N/A
• BP3: MM-VCEP deemed N/A for RUNX1
• BP1: MM-VCEP deemed N/A for RUNX1
• BP2: No evidence
• BP5: MM-VCEP deemed N/A for RUNX1
• BP7: N/A
• BA1: Variant meets PM2
• PP1: Not enough segregations (at least 3) reported in families in the literature to apply PP1.
• PP2: MM-VCEP deemed N/A for RUNX1
• PP3: N/A
• PP4: MM-VCEP deemed N/A for RUNX1
• PM1: N/A
• PM3: MM-VCEP deemed N/A for RUNX1
• PM5: N/A
• PM4: N/A
• PM6: No data currently available