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]
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Variant: NM_001754.4(RUNX1):c.56G>A (p.Arg19Lys)

CA10014724

409814 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 3f59c0c0-9bf7-40ae-af09-0ffa15ab278b
Approved on: 2024-08-12
Published on: 2024-08-12

HGVS expressions

NM_001754.4:c.56G>A
NM_001754.4(RUNX1):c.56G>A (p.Arg19Lys)
NC_000021.9:g.35048844C>T
CM000683.2:g.35048844C>T
NC_000021.8:g.36421141C>T
CM000683.1:g.36421141C>T
NC_000021.7:g.35343011C>T
NG_011402.2:g.940868G>A
ENST00000675419.1:c.56G>A
ENST00000300305.7:c.56G>A
ENST00000416754.1:c.56G>A
ENST00000437180.5:c.56G>A
ENST00000455571.5:c.56G>A
ENST00000475045.6:c.56G>A
ENST00000482318.5:c.56G>A
NM_001754.5:c.56G>A

Uncertain Significance

Met criteria codes 1
BP4
Not Met criteria codes 24
PS4 PS2 PS3 PS1 PP1 PP3 PP2 PP4 PM6 PM2 PM5 PM1 PM3 PM4 BA1 PVS1 BS4 BS3 BS1 BP1 BP2 BP3 BP5 BP7

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_001754.4(RUNX1):c.56G>A (p.Arg19Lys) is a missense variant predicted to cause substitution of arginine by lysine at amino acid 19 (p.R19K); note that this variant is in the 5' UTR, c.-161732G>A, of NM_001001890.3. The variant has been reported in a 69-year-old patient with NPM1-mutated, cytogenetically normal AML at a VAF=53% (PMID: 31367767) and in a patient with CMML (PMID: 24030381, Supplementary Table 2); however, germline origin is unclear for these cases. The highest population minor allele frequency in gnomAD v2 is 0.006966% (9/129192 alleles) in the non-Finnish European population, and the variant has also been reported in 1/1358 controls from a study evaluating 57 individuals with cutaneous melanoma and 2 other primaries (PMID: 29641532, Supplementary Table 3). To our knowledge, functional assays have not been reported for this variant, but the computational predictor REVEL gives a score of 0.456, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy-VCEP: BP4.
Met criteria codes
BP4
REVEL score = 0.456, 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
PS4
The variant has been reported in a 69yo patient with NPM1-mutated CN-AML at a VAF=53% (PMID: 31367767) and in a patient with CMML (PMID: 24030381, Supplementary Table 2); however, the germline origin of these cases is unclear. Note that the variant was also reported in 1/1358 controls and 0/57 individuals with cutaneous melanoma+2 other primaries (PMID: 29641532, Supplementary Table 3).
PS2
No definitively germline cases were found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS3
No functional data was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS1
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PP1
No familial data was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PP3
REVEL score = 0.456, 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
PP4
Not applicable
PM6
No definitively germline cases were found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PM2
gnomAD (v2): ALL: 0.003182% (9/282864) - NFE: 0.006966% (9/129192) gnomAD (v3): ALL: 0.003944% (6/152148) - NFE: 0.008819% (6/68034)
PM5
R19 variants are reported in COSMIC and/or Mastermind, but not at a high enough frequency that they would be likely classified as LP/P.
PM1
Not located at a hotspot (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R210, R204) or within residues 89-204.
PM3
Not applicable
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
gnomAD (v2): ALL: 0.003182% (9/282864) - NFE: 0.006966% (9/129192) gnomAD (v3): ALL: 0.003944% (6/152148) - NFE: 0.008819% (6/68034)
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No familial data was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS3
No functional data was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS1
gnomAD (v2): ALL: 0.003182% (9/282864) - NFE: 0.006966% (9/129192) gnomAD (v3): ALL: 0.003944% (6/152148) - NFE: 0.008819% (6/68034)
BP1
Not applicable
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
Not applicable
BP5
Not applicable
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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