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

CA410203419

561234 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: c169acf6-7c2b-48f0-82dd-85bb6bde1d1f

HGVS expressions

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

Likely Pathogenic

Met criteria codes 4
PS3 PP3 PM1 PM2_Supporting
Not Met criteria codes 22
PS2 PS4 PS1 PP1 PP4 PP2 PM5 PM4 PM3 PM6 PVS1 BA1 BS2 BS4 BS3 BS1 BP3 BP2 BP4 BP1 BP5 BP7

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
The c.330G>C (NM_001754.5) variant in RUNX1 is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 110 (p.K110N). This variant involves one of the hotspot residues that is defined as a mutational hotspot by the ClinGen MM-VCEP (PMID: 31648317; PMID: 10404214; PMID: 10620014; PMID: 11257229; PMID: 26010396) (PM1). The variant is absent from gnomAD v2, v3, and v4 with at least 20x coverage (PM2_Supporting). The variant has been reported in 4 individuals with AML, but variant origin is unclear (PMID: 10068652; PMID: 27288520; PMID: 31772163; PMID: 32696696) (PS4_Supporting is not met); the somatic variant has been reported in AML (PMID: 29472724), gMDS (PMID: 31772163), and TCGA bladder cancer (COSMIC ID: COSV55875639/cBioPortal) samples. 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) (PS3). Additional studies of the mutant protein in mouse bone marrow cells 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). Similarly, the computational predictor REVEL gives a score of 0.884, which is above the threshold of 0.88 (evidence that correlates with impact to RUNX1 function), and the splice site predictor SpliceAI indicated that the variant has no impact on splicing (PP3). In summary, this variant meets the criteria to be classified as a likely pathogenic for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PS3, PM1, PM2_Supporting, and PP3. (Version 2; date of approval)
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).
K83N was transduced into murine bone marrow via a retroviral vector and resulted in reduced GFP+ cells (median of 14% GFP+ cells), no effect on the lymphoid lineages, reduced ratio of erythroid to myeloid colonies, increased replating efficiencies and immortalization of cells, and the accumulation of myeloblasts and dysplastic progenitors. Finally, K83N with either T161A or T161A+N109D (alterations that reduce CBFβ-binding) did not change replating efficiencies or the amount of accumulation of progenitor cells, suggesting that immortalization is not necessarily due to a dominant-negative effect. PubMed:17234761
K83N was transduced into SC1 murine fibroblasts, and reduction of this variant's mRNA was seen upon transfection with short interfering-RNA (posttranscriptional silencing of target gene). K83N was transduced into HEK293T cells, and reduction of this variant's mRNA was seen upon transfection with short hairpin-RNA (longer-lasting gene silencing). These results were confirmed by RT-PCR and flow cytometry. PubMed:22649608
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). Additional missense predictions are reviewed in PMID: 32958805.
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).
PM2_Supporting
The variant is absent from gnomAD v2+v3+v4 (>20 coverage).
Not Met criteria codes
PS2
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS4
The variant of unclear origin has been reported in 4 individuals with AML (PMID: 10068652; PMID: 27288520; PMID: 31772163; PMID: 32696696), and the somatic variant has been reported in an AML (PMID: 29472724), an MDS (PMID: 31772163), and a TCGA bladder cancer (COSMIC ID: COSV55875639/cBioPortal).
PS1
The c.330G>T variant also results in p.K110N. This variant has at least been reported as a somatic alteration in an AML that also demonstrated LOH at this locus (pure tumor cells were sequenced after sorting) (PMID: 19773259), 2 breast cancers (PMID: 28481359; PMID: 30205045), and a lung adenocarcinoma (PMID: 31844068). It is classified as likely pathogenic by Invitae (ClinVar Variation ID: 1518631); it hasn't completed review by the MM-VCEP, but the rationale for pathogenicity is likely based on the functional data also available for c.330G>C.
PP1
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
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.
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
Not applicable
PM6
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
The variant is absent from gnomAD v2+v3+v4 (>20 coverage).
BS2
This rule is not applicable for MM-VCEP
BS4
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
The variant is absent from gnomAD v2+v3+v4 (>20 coverage).
BP3
Not applicable
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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). Additional missense predictions are reviewed in PMID: 32958805.
BP1
Not applicable
BP5
Not applicable
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2023-12-09
Published on: 2023-12-09
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