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
  • 'cspec' property is found but contains no ID!
  • No CSPEC computer assertion could be determined for this classification!
  • See Evidence submitted by expert panel for details.

Variant: NM_001754.5(RUNX1):c.856C>A (p.Gln286Lys)

CA10014280

575500 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 33257ee1-c050-4411-b952-c5561175eb09
Approved on: 2024-09-11
Published on: 2024-09-11

HGVS expressions

NM_001754.5:c.856C>A
NM_001754.5(RUNX1):c.856C>A (p.Gln286Lys)
NC_000021.9:g.34799412G>T
CM000683.2:g.34799412G>T
NC_000021.8:g.36171709G>T
CM000683.1:g.36171709G>T
NC_000021.7:g.35093579G>T
NG_011402.2:g.1190300C>A
ENST00000675419.1:c.856C>A
ENST00000300305.7:c.856C>A
ENST00000344691.8:c.775C>A
ENST00000399240.5:c.583C>A
ENST00000437180.5:c.856C>A
ENST00000482318.5:c.*446C>A
NM_001001890.2:c.775C>A
NM_001754.4:c.856C>A
NM_001001890.3:c.775C>A
More

Likely Benign

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

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
NM_001754.5(RUNX1):c.856C>A (p.Gln286Lys) is a missense variant which is predicted to cause substitution of glutamine by lysine at amino acid 286. The highest population minor allele frequency in gnomAD v2 is 0.00003096 (4/129198 alleles) in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). The germline variant has been reported in a patient with JMML but without features consistent with the RUNX1 phenotypic criteria (PMID: 20955399), and the variant of unclear origin was reported in a patient with cytopenia (PMID: 32241844). In vitro functional studies using HEK293T and HEL cells confirmed the expression of the mutant protein, and the variant demonstrated 80-115% transactivation activity for the CSF1R and MYL9 promoters (PMID: 35026845) (BS3_Supporting). This aligns with the computational predictor, REVEL, which gives a score of 0.152 that is below the threshold of 0.50 and, thus, evidence that does not predict a damaging effect on RUNX1 function; the splice site predictor, SpliceAI, which gives a score of <0.20, also indicates that the variant has no impact on splicing (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3_supporting, BP4.
Met criteria codes
BS3_Supporting
In vitro functional studies using HEK293T and HEL cells confirmed the expression of the mutant protein (Supplementary Figures 5+7), and the variant demonstrated 80-115% transactivation activity for the CSF1R and MYL9 promoters (Supplementary Figures 1-2) (PMID: 35026845).
BP4
REVEL score = 0.152, which is less than the v2 threshold of 0.50. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS4
The germline variant has been reported in a patient with JMML (PMID: 20955399), and the variant of unclear origin was reported in a patient with cytopenia (PMID: 32241844).
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
- gnomAD (v2): ALL: 0.001414% (4/282898) - NFE: 0.003096% (4/129198) - gnomAD (v3): ALL: 0.0006570% (1/152212) - NFE: 0.001470% (1/68046)
PP1
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PP4
Not applicable
PP3
REVEL score = 0.152, which is not higher than the v2 threshold of 0.88. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
PP2
Not applicable
PM6
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PM2
- gnomAD (v2): ALL: 0.001414% (4/282898) - NFE: 0.003096% (4/129198) - gnomAD (v3): ALL: 0.0006570% (1/152212) - NFE: 0.001470% (1/68046)
PM3
Not applicable
PM5
R226/R259 variants have not been reported in COSMIC or Mastermind.
PM1
Not located at a hotspot (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R210, R204) or within residues 89-204.
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS1
- gnomAD (v2): ALL: 0.001414% (4/282898) - NFE: 0.003096% (4/129198) - gnomAD (v3): ALL: 0.0006570% (1/152212) - NFE: 0.001470% (1/68046)
BS2
Not applicable
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
Not applicable
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
Not applicable
BP3
Not applicable
Curation History
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