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]
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  • See Evidence submitted by expert panel for details.

CA10014591

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 5a3a40ef-ba6a-45c4-9b10-6ea243107987
Approved on: 2022-01-20
Published on: 2022-06-30

HGVS expressions

NM_001754.5:c.110G>T
NC_000021.9:g.34887084C>A
CM000683.2:g.34887084C>A
NC_000021.8:g.36259381C>A
CM000683.1:g.36259381C>A
NC_000021.7:g.35181251C>A
NG_011402.2:g.1102628G>T
ENST00000675419.1:c.110G>T
ENST00000300305.7:c.110G>T
ENST00000344691.8:c.29G>T
ENST00000358356.9:c.29G>T
ENST00000399237.6:c.74G>T
ENST00000399240.5:c.29G>T
ENST00000437180.5:c.110G>T
ENST00000455571.5:c.71G>T
ENST00000475045.6:c.110G>T
ENST00000482318.5:c.59-6371G>T
NM_001001890.2:c.29G>T
NM_001122607.1:c.29G>T
NM_001754.4:c.110G>T
NM_001001890.3:c.29G>T
NM_001122607.2:c.29G>T

Uncertain Significance

The Expert Panel has overridden the computationally generated classification - "[unknown]"
Not Met criteria codes 26
PS2 PS1 PS3 PS4 PP1 PP4 PP3 PP2 PM6 PM2 PM5 PM1 PM3 PM4 BA1 PVS1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
The c.110G>T variant in RUNX1 is a missense variant predicted to cause substitution of serine by isoleucine at amino acid 37 (p.Ser37Ile). The highest population minor allele frequency in gnomAD v2 is 0.00005863 (2/34114 alleles) in the AMR population. The germline variant has not been published or reported in any affected individuals, nor have other variants that result in the same amino acid change or different likely pathogenic/pathogenic missense variants at the same codon. The computational predictor, REVEL, gives a score of 0.601, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function. Note that the results from the in silico splicing predictor, SpliceAI, supports that this variant does not affect splicing. In summary, this variant meets the criteria to be classified as VUS 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: None.
Not Met criteria codes
PS2
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS1
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS3
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS4
The variant has been reported in a patient with AML, but germline origin is unclear (Onecha de la Fuenta, 2019, Thesis).
PP1
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PP4
Not applicable
PP3
REVEL score = 0.601, which is not higher than the v2 threshold of 0.88 nor is it less than the v2 threshold of 0.50. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
PP2
Not applicable
PM6
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PM2
gnomAD (v2): ALL: 0.0008744% (2/228722) - AMR: 0.005863% (2/34114) gnomAD (v3): ALL: 0.0006570% (1/152208) - AMR: 0.006542% (1/15286)
PM5
S37/S10 variants are reported in Mastermind (not in COSMIC), but not in germline cases or at a high enough frequency that they would be likely classified as LP/P.
PM1
Not located at a hotspot (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R210, R204) or within residues 89-204.
PM3
Not applicable
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
gnomAD (v2): ALL: 0.0008744% (2/228722) - AMR: 0.005863% (2/34114) gnomAD (v3): ALL: 0.0006570% (1/152208) - AMR: 0.006542% (1/15286)
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
Not applicable
BS4
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS3
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS1
gnomAD (v2): ALL: 0.0008744% (2/228722) - AMR: 0.005863% (2/34114) gnomAD (v3): ALL: 0.0006570% (1/152208) - AMR: 0.006542% (1/15286)
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 = 0.601, which is not less than the v2 threshold of 0.50 nor is it higher than the v2 threshold of 0.88. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
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
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