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

UUID: c3870801-0fcc-45c8-9383-0ae10065097d

Approved on: 2019-07-26

Published on: 2019-08-02

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
ENST00000675419.1:c.253C>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
NM_001001890.2:c.172C>A
NM_001122607.1:c.172C>A
NM_001001890.3:c.172C>A
NM_001122607.2:c.172C>A
NM_001754.5:c.253C>A

Likely Benign

• Met criteria codes: PP3 BS1 BS3

• Not Met criteria codes: PS1 PS2 PS3 PS4 BA1 PP1 PP2 PP4 PM6 PM2 PM1 PM3 PM5 PM4 PVS1 BS4 BS2 BP5 BP7 BP4 BP3 BP1 BP2

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

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

• PP3: REVEL: 0.852 >0.75
• BS1: gnomAD Allele Frequency of East Asian Subpopulation: 0.00043 (8 out of 18768 Alleles) > 0.00015
• BS3: Transactivation assays demonstrate normal transactivation (80-114% of WT). Secondary assays demonstrate normal DNA binding, CBFβ binding and sub-cellular localization.

Not Met criteria codes

• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No evidence
• 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).
• BA1: gnomAD Allele Frequency of East Asian Subpopulation: 0.00043 (8 out of 18768 Alleles) < 0.0015
• PP1: No evidence
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No evidence
• PM2: 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
• PM3: Not applicable
• 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
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No evidence
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: 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
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No evidence