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 computed assertion could be determined for this classification!

Variant: NM_001754.5(RUNX1):c.1198_1201dup (p.Pro401fs)

CA658824658

561223 (ClinVar)

Gene: RUNX1 (HGNC:861)
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome (MONDO:0011071)
Inheritance Mode: Autosomal dominant inheritance
UUID: 9aa88b89-e4e4-4fa5-aca4-4ce8f0b31372
Approved on: 2026-10-15
Published on: 2026-10-15

HGVS expressions

NM_001754.5(RUNX1):c.1198_1201dup (p.Pro401fs)
NM_001754.5:c.1198_1201dup
NC_000021.9:g.34792379_34792382dup
CM000683.2:g.34792379_34792382dup
NC_000021.8:g.36164676_36164679dup
CM000683.1:g.36164676_36164679dup
NC_000021.7:g.35086546_35086549dup
NG_011402.2:g.1197332_1197335dup
ENST00000675419.1:c.1198_1201dup
ENST00000300305.7:c.1198_1201dup
ENST00000344691.8:c.1117_1120dup
ENST00000399240.5:c.925_928dup
ENST00000437180.5:c.1198_1201dup
ENST00000482318.5:c.*788_*791dup
NM_001001890.2:c.1117_1120dup
NM_001754.4:c.1198_1201dup
NM_001001890.3:c.1117_1120dup
More

Likely Pathogenic

Met criteria codes 3
PVS1_Strong PM5_Supporting PM2_Supporting
Not Met criteria codes 23
PS2 PS4 PS3 PS1 BA1 PP4 PP1 PP3 PP2 PM6 PM3 PM1 PM4 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RUNX1 Version 3.1

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
NM_001754.5(RUNX1):c.1198_1201dup (p.Pro401LeufsTer?) is a frameshift variant which is not predicted to undergo NMD (PVS1_Strong). This variant is downstream of c.98 (PM5_Supporting) and is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM5_Supporting, PM2_Supporting.
Met criteria codes
PVS1_Strong
Duplication that is not expected to result in NMD, but is expected to alter the transactivation domain, inhibitory domain, and/or the VWRPY motif, as well as elongate the protein.
PM5_Supporting
This variant is a frameshift variant that is downstream of c.98 (PM5_Supporting).
PM2_Supporting
This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).
Not Met criteria codes
PS2
De novo data for this variant has not been reported in literature.
PS4
No patients have been described in the literature with this variant and a relevant phenotype (i.e. thrombocytopenia, platelet ultrastructural and/or functional defects, or hematological malignancy). However, it has been described in a patient with a telomere length of <1st percentile; upon follow-up with the authors, Dr. Mary Armanios indicated that the patient also had thrombocytopenia and the cDNA of this variant is c.1198_1201dupTCGC, but the variant has not been confirmed in the germline.
PS3
Although some other C-terminal frameshift alterations (i.e. stop-loss variants) show functional evidence of loss-of-function with a dominant negative effect, specific data for this particular variant was not found.
“Of the 28 frameshift mutations, 7 generated truncated peptides with complete or partial deletion of the RHD, 4 generated truncated peptides with intact RHD region, and the remaining 17 generated elongated proteins with intact RHD region (Figure 1); all were suggested to abolish transactivation potential resulting from complete or partial loss of TAD,34 with the exception of P375fsX570, which retained the intact TAD.” PubMed:19808697
“The C-terminal frameshift mutants all displayed strong interaction with DNA and CBFβ, but only weak activities on C-FMS induction, except the Asp424Glyfs*149 mutant which does not affect the TAD. The dominant-negative effects of these C-terminal frameshift mutants were demonstrated by Harada and colleagues previously (2, 10), and our data were consistent with their observation.” PubMed:25840971
“All of the C-terminal mutations (cases 24-32) [(24-31 in patients with sporadic MDS and 1 patient with secondary MDS)] resulted in frame shifts similar to the Runx2 mutations identified in CCD [(Fig. 7)]... Analysis of C-terminal mutants provided 3 additional types of mutation: attenuated DNA-binding potential without trans-activation potential (Type a-2, mutants 25, 31, and 32), enhanced DNA-binding ability but no trans-activation potential (Type a-3, mutants 24, 26, 27, and 30b), and DNA-binding ability equivalent to wild-type AML1 but no trans-activation potential (Type a-4, mutant 30a) [(Fig. 6)].” PubMed:14615365
PS1
This variant is not a missense, or synonymous variant.
BA1
This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
PP4
Not applicable
PP1
Segregation data for this variant has not been reported in literature.
PP3
This variant does not have applicable in-silico data available.
PP2
Not applicable
PM6
De novo data for this variant has not been reported in literature.
PM3
Not applicable
PM1
This variant is not a missense variant.
PM4
This variant is not an in-frame deletion/insertion.
BS2
Not applicable
BS4
Segregation data for this variant has not been reported in literature.
BS3
This variant has not been featured in in vitro or in vivo functional studies showing a damaging effect on the gene or gene product.
“Of the 28 frameshift mutations, 7 generated truncated peptides with complete or partial deletion of the RHD, 4 generated truncated peptides with intact RHD region, and the remaining 17 generated elongated proteins with intact RHD region (Figure 1); all were suggested to abolish transactivation potential resulting from complete or partial loss of TAD,34 with the exception of P375fsX570, which retained the intact TAD.” PubMed:19808697
“The C-terminal frameshift mutants all displayed strong interaction with DNA and CBFβ, but only weak activities on C-FMS induction, except the Asp424Glyfs*149 mutant which does not affect the TAD. The dominant-negative effects of these C-terminal frameshift mutants were demonstrated by Harada and colleagues previously (2, 10), and our data were consistent with their observation.” PubMed:25840971
“All of the C-terminal mutations (cases 24-32) [(24-31 in patients with sporadic MDS and 1 patient with secondary MDS)] resulted in frame shifts similar to the Runx2 mutations identified in CCD [(Fig. 7)]... Analysis of C-terminal mutants provided 3 additional types of mutation: attenuated DNA-binding potential without trans-activation potential (Type a-2, mutants 25, 31, and 32), enhanced DNA-binding ability but no trans-activation potential (Type a-3, mutants 24, 26, 27, and 30b), and DNA-binding ability equivalent to wild-type AML1 but no trans-activation potential (Type a-4, mutant 30a) [(Fig. 6)].” PubMed:14615365
BS1
This variant does not have a MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental dataset.
BP5
Not applicable
BP7
This variant is not a synonymous or intronic variant.
BP2
This variant has not been observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
BP3
This rule is not applicable for MM-VCEP.
BP4
This variant does not have applicable in-silico data available.
BP1
Not applicable
Curation History
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