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]
Link to SEPIO compliant JSON-LD document
  • See Evidence submitted by expert panel for details.

Variant: NM_001754.4(RUNX1):c.253C>A (p.His85Asn)

CA123975

14469 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: c3870801-0fcc-45c8-9383-0ae10065097d

HGVS expressions

NM_001754.4:c.253C>A
NM_001754.4(RUNX1):c.253C>A (p.His85Asn)
NC_000021.9:g.34886941G>T
CM000683.2:g.34886941G>T
NC_000021.8:g.36259238G>T
CM000683.1:g.36259238G>T
NC_000021.7:g.35181108G>T
NG_011402.2:g.1102771C>A
NM_001001890.2:c.172C>A
NM_001122607.1:c.172C>A
ENST00000300305.7:c.253C>A
ENST00000344691.8:c.172C>A
ENST00000358356.9:c.172C>A
ENST00000399237.6:c.217C>A
ENST00000399240.5:c.172C>A
ENST00000437180.5:c.253C>A
ENST00000455571.5:c.214C>A
ENST00000482318.5:c.59-6228C>A

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"
Met criteria codes 3
BS3 BS1 PP3
Not Met criteria codes 15
PM6 PM2 PM5 PM4 PM1 PVS1 BA1 BS4 BP7 BP4 BP2 PS1 PS3 PS4 PP1

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
The NM_001754.4:c.253C>A (p.His85Asn) variant has a MAF of 0.00043 (0.043%, 8/18,768 alleles) in the East Asian subpopulation of the gnomAD cohort that is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense variant has a REVEL score >0.75 (0.852) (PP3). Transactivation assays demonstrating normal transactivation (80-115% of wt) and data from secondary assays demonstrate normal DNA binding, CBFβ binding and sub-cellular localization (BS3; PMID: 23817177, PMID: 10068652). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BS3, PP3.
Met criteria codes
BS3
Transactivation assays demonstrate normal transactivation (80-114% of WT). Secondary assays demonstrate normal DNA binding, CBFβ binding and sub-cellular localization.
Transactivation assays demonstrate normal transactivation (80-114% of WT). Secondary assays demonstrate normal DNA binding and sub-cellular localization. PubMed:10068652
Transactivation assays demonstrate normal transactivation (80-114% of WT). Secondary assays demonstrate normal DNA binding, CBFβ binding and sub-cellular localization. PubMed:23817177
BS1
gnomAD Allele Frequency of East Asian Subpopulation: 0.00043 (8 out of 18768 Alleles) > 0.00015
PP3
REVEL: 0.852 >0.75
Not Met criteria codes
PM6
No evidence
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
gnomAD Allele Frequency of East Asian Subpopulation: 0.00043 (8 out of 18768 Alleles) < 0.0015
BS4
No evidence
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No evidence
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
Although this mutant disrupts MLL binding, which impairs proper H3K4 histone methylation, it is not a qualified functional assay based on the RUNX1 specific PS3/BS3 rule. Moreover, another well-established benign variant L56S also impairs MLL binding (PMID: 23817177).
PS4
Osato et al. reported an adult patient carrying this variant with acute myeloid leukemia (AML) of the M0 subtype (PMID: 10068652). However, the germline nature of the variant was not definitively determined. This variant has also been reported in an infant diagnosed with transient myeloproliferative disorder and Down syndrome whose phenotype doesn’t meet any of the RUNX1 phenotype criteria (PMID: 12200707).
Osato et al. reported an adult patient carrying this variant with acute myeloid leukemia (AML) of the M0 subtype. However, the germline nature of the variant was not definitively determined. PubMed:10068652
This variant has also been reported in an infant diagnosed with transient myeloproliferative disorder and Down syndrome whose phenotype doesn’t meet any of the RUNX1 phenotype criteria. PubMed:12200707
PP1
No evidence
Approved on: 2019-07-26
Published on: 2019-08-02
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