Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_001754.5(RUNX1):c.749G>A

CA10014362

239055 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ec8b74dd-6ae1-4eac-9348-d770372d4bc6
Approved on: 2024-06-24
Published on: 2024-06-24

HGVS expressions

NM_001754.5:c.749G>A
NM_001754.5(RUNX1):c.749G>A
NC_000021.9:g.34834466C>T
CM000683.2:g.34834466C>T
NC_000021.8:g.36206763C>T
CM000683.1:g.36206763C>T
NC_000021.7:g.35128633C>T
NG_011402.2:g.1155246G>A
ENST00000675419.1:c.749G>A
ENST00000300305.7:c.749G>A
ENST00000344691.8:c.668G>A
ENST00000358356.9:c.668G>A
ENST00000399237.6:c.713G>A
ENST00000399240.5:c.532+25008G>A
ENST00000437180.5:c.749G>A
ENST00000469087.1:n.285G>A
ENST00000482318.5:c.*339G>A
NM_001001890.2:c.668G>A
NM_001122607.1:c.668G>A
NM_001754.4:c.749G>A
NM_001001890.3:c.668G>A
NM_001122607.2:c.668G>A
More

Likely Benign

Met criteria codes 2
BS3 BP4
Not Met criteria codes 24
PP1 PP4 PP3 PP2 PM1 PM5 PM4 PM3 PM6 PM2 BA1 BS4 BS1 BS2 PVS1 BP7 BP5 BP3 BP2 BP1 PS1 PS2 PS3 PS4

Evidence Links 0

Expert Panel

Criteria Specification Information

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

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
The c.749G>A variant in RUNX1 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 250 (p.R250H). A luciferase reporter assaying in U937 cells showed that this variant has normal transcriptional activity, and an EMSA assay using COS7 cells showed that this variant has normal DNA-binding and β-subunit interaction with normal nuclear localization in NIH3T3 cells, indicating that this variant does not impact protein function (PMID: 23817177) (BS3). The computational predictor, REVEL, gives a score of 0.488, which is below the threshold of 0.50, evidence that suggests no impact on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BS3 and BP4.
Met criteria codes
BS3
The variant exhibits normal transcriptional activity in a luciferase reporter assay using U937 cells (80-115% of WT activity, Fig. 4), normal DNA-binding and β-subunit interaction in an EMSA assay using Cos7 cells (Fig. 2), and appropriate nuclear localization in NIH3T3 cells (PMID: 23817177-Table 1).
BP4
REVEL score = 0.488, which is less than the v2 threshold of 0.50. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
Not Met criteria codes
PP1
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PP4
Not applicable
PP3
REVEL score = 0.488, which is less than the v2 threshold of 0.88. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
PP2
Not applicable
PM1
Not located at a hotspot (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R210, R204) or within residues 89-204.
PM5
R250C/R223C has been reported the most in COSMIC and Mastermind, but not as definitively germline cases (HGMD).
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.
PM2
gnomAD (v2): ALL: 0.003911% (11/281252) - NFE: 0.007028% (9/128052) - AFR: 0.004018% (1/24890) - AMR: 0.002823% (1/35424) gnomAD (v3): ALL: 0.004628% (7/151250) - NFE: 0.007366% (5/67878) - AMR: 0.006594% (1/15166) - AFR: 0.002435% (1/41064)
BA1
gnomAD (v2): ALL: 0.003911% (11/281252) - NFE: 0.007028% (9/128052) - AFR: 0.004018% (1/24890) - AMR: 0.002823% (1/35424) gnomAD (v3): ALL: 0.004628% (7/151250) - NFE: 0.007366% (5/67878) - AMR: 0.006594% (1/15166) - AFR: 0.002435% (1/41064)
BS4
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS1
gnomAD (v2): ALL: 0.003911% (11/281252) - NFE: 0.007028% (9/128052) - AFR: 0.004018% (1/24890) - AMR: 0.002823% (1/35424) gnomAD (v3): ALL: 0.004628% (7/151250) - NFE: 0.007366% (5/67878) - AMR: 0.006594% (1/15166) - AFR: 0.002435% (1/41064)
BS2
Not applicable
PVS1
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
BP5
Not applicable
BP3
Not applicable
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
Not applicable
PS1
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS2
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
The variant (c.668G>A/p.R223H) was reported in a Caucasian female with pancytopenia without relevant family history, but germline origin was not confirmed in an ideal sample type or via familial testing (ClinVar/GTR Lab ID: 26957). The variant was also detected in the bone marrow (germline origin not confirmed) of a 69yo male with urinary bladder cancer, who developed t-MDS (RAEB) 29 months after radiation therapy and died 2 months after (PMID: 15142876), in an HPV-positive head and neck squamous cell carcinoma (PMID: 23718828-Additional File 1, cited by PMID: 26353884), and in a patient with rectal cancer at 42 and an MSS uterine cancer at 49, whose sister had a brain tumor (PMID: 28873162 - Supplement 2, Memorial Sloan Kettering).
Curation History
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