Variant: NM_001754.5(RUNX1):c.330G>T (p.Lys110Asn)

CA410203418

1518631 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 6650db7a-2a3c-48be-9f7f-227ccbe66979

Approved on: 2023-12-09

Published on: 2023-12-09

HGVS expressions

NM_001754.5:c.330G>T
NM_001754.5(RUNX1):c.330G>T (p.Lys110Asn)
NC_000021.9:g.34886864C>A
CM000683.2:g.34886864C>A
NC_000021.8:g.36259161C>A
CM000683.1:g.36259161C>A
NC_000021.7:g.35181031C>A
NG_011402.2:g.1102848G>T
ENST00000675419.1:c.330G>T
ENST00000300305.7:c.330G>T
ENST00000344691.8:c.249G>T
ENST00000358356.9:c.249G>T
ENST00000399237.6:c.294G>T
ENST00000399240.5:c.249G>T
ENST00000437180.5:c.330G>T
ENST00000455571.5:c.291G>T
ENST00000482318.5:c.59-6151G>T
NM_001001890.2:c.249G>T
NM_001122607.1:c.249G>T
NM_001754.4:c.330G>T
NM_001001890.3:c.249G>T
NM_001122607.2:c.249G>T

Likely Pathogenic

• Met criteria codes: PS3 PP3 PM2_Supporting PM1

• Not Met criteria codes: PS2 PS4 PS1 PVS1 PP1 PP4 PP2 PM5 PM3 PM4 PM6 BA1 BS3 BS4 BS1 BS2 BP7 BP5 BP2 BP3 BP4 BP1

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.330G>T (p.Lys110Asn) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). REVEL score is greater than 0.88 (0.884) and SpliceAI is not greater than 0.38 (0.00) (PP3). This variant affects one of the hotspot (K110) residues established by the MM-VCEP for RUNX1 (PM1). The c.328A>G variant is the same amino acid change (p.K110E) as a previously established pathogenic variant (ClinVar ID 14465) curated using MM-VCEP rules for RUNX1 (PS1). 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: PM2_supporting, PP3, PM1, PS1.

Met criteria codes

• PS3: The variant in a transactivation assay using the M-CSF promoter exhibited a 70% reduction; the mutant protein was also unable to bind DNA whether or or not in the presence of the CBFβ subunit, without affecting CBFβ heterodimerization and nuclear localization (PMID: 10068652; PMID: 11830488). Additional studies of the mutant protein showed that it decreases the ratio of erythroid to myeloid colonies, results in immortalization of cells, and the accumulation of myeloblasts and dysplastic progenitors (PMID: 17234761).
• PP3: REVEL score = 0.884, which is higher than the v2 threshold of 0.88. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
• PM2_Supporting: Completely absent from gnomAD v2+v3+v4 with a mean coverage of at least 20X.
• PM1: This variant affects one of the hotspot residues (K110) established by the MM-VCEP for RUNX1 (PMID: 31648317; PMID: 10404214; PMID: 10620014; PMID: 11257229; PMID: 26010396).

Not Met criteria codes

• PS2: No case studies found
• PS4: No case studies found
• PS1: The c.330G>C variant also results in p.K110N, and it is classified as likely pathogenic per the MM-VCEP. However, as there is functional data for K110N (not specific to cDNA), this code is not applied.
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No case studies found
• PP4: Not applicable
• PP2: Not applicable
• PM5: K110E has been classified as pathogenic by the MM-VCEP. However, glutamic acid and asparagine have differing properties. In addition, this is a hotspot residue. Although not directly stated in the current version of the rules, PM5 should conservatively not be applied.
• PM3: Not applicable
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No case studies found
• BA1: Completely absent from gnomAD v2+v3+v4 with a mean coverage of at least 20X.
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No case studies found
• BS1: Completely absent from gnomAD v2+v3+v4 with a mean coverage of at least 20X.
• BS2: Not applicable
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: Not applicable
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: Not applicable
• BP4: REVEL score = 0.884, which is not less than the v2 threshold of 0.50. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
• BP1: Not applicable