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.737C>T (p.Thr246Met)

CA10014365

239054 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: feaa41a1-754f-4593-a467-193bca1ccef4
Approved on: 2024-07-11
Published on: 2024-07-11

HGVS expressions

NM_001754.5:c.737C>T
NM_001754.5(RUNX1):c.737C>T (p.Thr246Met)
NC_000021.9:g.34834478G>A
CM000683.2:g.34834478G>A
NC_000021.8:g.36206775G>A
CM000683.1:g.36206775G>A
NC_000021.7:g.35128645G>A
NG_011402.2:g.1155234C>T
ENST00000675419.1:c.737C>T
ENST00000300305.7:c.737C>T
ENST00000344691.8:c.656C>T
ENST00000358356.9:c.656C>T
ENST00000399237.6:c.701C>T
ENST00000399240.5:c.532+24996C>T
ENST00000437180.5:c.737C>T
ENST00000469087.1:n.273C>T
ENST00000482318.5:c.*327C>T
NM_001001890.2:c.656C>T
NM_001122607.1:c.656C>T
NM_001754.4:c.737C>T
NM_001001890.3:c.656C>T
NM_001122607.2:c.656C>T
More

Likely Benign

Met criteria codes 2
BP4 BS3_Supporting
Not Met criteria codes 24
BS2 BS4 BS1 BP2 BP3 BP1 BP5 BP7 PS2 PS4 PS3 PS1 BA1 PVS1 PP4 PP1 PP3 PP2 PM3 PM1 PM4 PM5 PM6 PM2

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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
NM_001754.5(RUNX1):c.737C>T (p.Thr246Met) is a missense variant. The highest population minor allele frequency in gnomAD v3.1.2 is 0.00002942 (2/67986 alleles) in the European (non-Finnish) population (PM2_supporting, BS1, and BA1 not met). This missense variant has a REVEL score < 0.50 (0.4) and a SpliceAI score ≤ 0.20 (0.01) (BP4). Transactivation assays in HeLa cells showed no significant decrease in transactivation compared to the WT allele (88.74% with luciferase reporter and 112.2% with GMZA reporter), indicating that this variant does not impact protein function (PMID 34166225) (BS3_supporting). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3_supporting, BP4.
Met criteria codes
BP4
This missense variant has a REVEL score < 0.50 (0.4) and SpliceAI score is ≤ 0.20 (0.01) (BP4).
BS3_Supporting
Transactivation assay in Hela cells showed no significant decrease of transactivation compared to WT allele (88.74% with luciferase reporter and 112.2% with GMZA reporter) indicating that this variant does not impact protein function (PMID 34166225) (BS3_supporting).
Not Met criteria codes
BS2
This rule is not applicable to the MMVCEP.
BS4
To our knowledge, no publication has reported this information to date.
BS1
The highest population minor allele frequency in gnomAD v3.1.2 is 0.00002942 (2/67986 alleles) in European (non-Finnish) population. PM2_Supporting, BS1, and BA1 are not met. max MAF 0.0001388 in gnomAD v2.1.1 (1/7204 alleles, Other)
BP2
To our knowledge, no publication has reported this information to date.
BP3
This rule is not applicable to the MMVCEP.
BP1
This rule is not applicable to the MMVCEP.
BP5
This rule is not applicable to the MMVCEP.
BP7
This variant is a missense.
PS2
To our knowledge, no publication has reported this information to date.
PS4
Variant is present more then once in gnomAD.
PS3
Transactivation assay in Hela cells showed no significant decrease of transactivation compared to WT allele (88.74% with luciferase reporter and 112.2% with GMZA reporter) indicating that this variant does not impact protein function (PMID 34166225)(BS3_moderate). + protein level similaire > 2nd assay?
PS1
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
This variant is a missense.
PP4
One entry in clinvar but no information on phenotype. One patient reported with an ALL in the literature (PMID: 34166225).
PP1
To our knowledge, no publication has reported this information to date.
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
This rule is not applicable to the MMVCEP.
PM3
This rule is not applicable to the MMVCEP.
PM1
This variant does not reside within a region of RUNX1 that is defined as a mutational hotspot or critical functional domain by the ClinGen MMVCEP.
PM4
This variant is a missense.
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
To our knowledge, no publication has reported this information to date.
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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