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
  • No CSPEC related information was provided by the message!
  • See Evidence submitted by expert panel for details.

Variant: NM_001754.4(RUNX1):c.280A>C (p.Ser94Arg)

CA16608536

389962 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: c44fff55-9f09-4d8d-b8f6-7dff5f68e0c0

HGVS expressions

NM_001754.4:c.280A>C
NM_001754.4(RUNX1):c.280A>C (p.Ser94Arg)
NC_000021.9:g.34886914T>G
CM000683.2:g.34886914T>G
NC_000021.8:g.36259211T>G
CM000683.1:g.36259211T>G
NC_000021.7:g.35181081T>G
NG_011402.2:g.1102798A>C
ENST00000675419.1:c.280A>C
ENST00000300305.7:c.280A>C
ENST00000344691.8:c.199A>C
ENST00000358356.9:c.199A>C
ENST00000399237.6:c.244A>C
ENST00000399240.5:c.199A>C
ENST00000437180.5:c.280A>C
ENST00000455571.5:c.241A>C
ENST00000482318.5:c.59-6201A>C
NM_001001890.2:c.199A>C
NM_001122607.1:c.199A>C
NM_001001890.3:c.199A>C
NM_001122607.2:c.199A>C
NM_001754.5:c.280A>C
NM_001754.5(RUNX1):c.280A>C (p.Ser94Arg)

Likely Pathogenic

Met criteria codes 4
PS3 PM2 PS4_Supporting PP3
Not Met criteria codes 22
PS1 PS2 PM3 PM5 PM4 PM1 PM6 BA1 PVS1 BP2 BP3 BP4 BP1 BP5 BP7 BS2 BS4 BS3 BS1 PP4 PP1 PP2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
The c.280A>C (p.Ser94Arg) RUNX1 variant is located within the RUNT homology domain but not within a mutational hotspot. Transactivation assays demonstrate reduced transactivation (<20% of wt) and data from a b-heterodimerization assay demonstrate loss of b-heterodimerization (PS3; unpublished data and PMID: 23817177). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; internal laboratory data, VCV000389962.2). This variant is absent from gnomAD (PM2) and has a REVEL score >0.75 (0.947) (PP3). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PS4_supporting, PM2, PP3.
Met criteria codes
PS3
The variant shows less than 20% transcriptional activity compared to wt using the BXH2-LTR-luc promoter with PEBP2b in U937 cells (unpublished data). It also shows a loss of b-heterodimerization (PMID 23817177).
PM2
Completely absent from gnomAD.
PS4_Supporting
Male proband with AML diagnosed at age 44.
PP3
REVEL score is 0.947.
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 code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
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
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
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
BP2
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
BP4
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
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
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
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
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.