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.1270T>C (p.Ser424Pro)

CA410147564

970259 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 4a2f5955-e2f0-466b-92a1-f20b7be3aa1b
Approved on: 2024-11-13
Published on: 2024-11-13

HGVS expressions

NM_001754.5:c.1270T>C
NM_001754.5(RUNX1):c.1270T>C (p.Ser424Pro)
NC_000021.9:g.34792308A>G
CM000683.2:g.34792308A>G
NC_000021.8:g.36164605A>G
CM000683.1:g.36164605A>G
NC_000021.7:g.35086475A>G
NG_011402.2:g.1197404T>C
ENST00000675419.1:c.1270T>C
ENST00000300305.7:c.1270T>C
ENST00000344691.8:c.1189T>C
ENST00000399240.5:c.997T>C
ENST00000437180.5:c.1270T>C
ENST00000482318.5:c.*860T>C
NM_001001890.2:c.1189T>C
NM_001754.4:c.1270T>C
NM_001001890.3:c.1189T>C
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Uncertain Significance

Met criteria codes 1
BP4
Not Met criteria codes 25
BA1 BS2 BS4 BS3 BS1 BP7 BP5 BP2 BP3 BP1 PS4 PS2 PS3 PS1 PP1 PP4 PP3 PP2 PVS1 PM5 PM1 PM3 PM4 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

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
NM_001754.5(RUNX1):c.1270T>C (p.Ser424Pro) is a missense variant predicted to cause the substitution of serine by proline at amino acid 424 (p.S424P). This variant is absent from gnomAD v2, but in gnomAD v3, the highest population minor allele frequency is 0.07016% (4/4276 alleles) in the East Asian population, and in gnomAD v4, it is 2.641% (624/23626 alleles) in the East Asian population. Both frequencies are higher than the overall allele frequency of all disease-causing alleles derived by the ClinGen Myeloid Malignancy-VCEP. However, genomes failed a quality filter (AS_VQSR) in gnomAD v3 and v4, allele balance is heavily skewed, and site quality seems lower compared to some common, known pathogenic variants (BA1 not met). This variant has been reported in a 59-year-old female with thrombocytopenia and a secondary defect, who also carried RUNX1 c.1256T>G (p.Val419Gly) (phasing unclear) and a 2.5 Mb deletion including FLI1, although the germline origin was presumed rather than confirmed by tissue or familial testing (PMID: 32935436). Additionally, one individual in a Japanese family with B-ALL, likely due to PAX5 G183R, was found to carry this variant, while two siblings were negative (PMID: 35902733). Another patient reportedly with hereditary thrombocytopenia and hematological cancer predisposition associated with RUNX1 carried this variant in the germline, but an unspecified number of affected relatives in the family were negative (ClinVar Accession: SCV002515682.3). The variant has also been reported in patients with AML (PMID: 36900179), MDS (PMID: 36932114), and other tumors (PMID: 30239046; PMID: 30246500; PMID: 32943879; PMID: 35626111; PMID: 37160887; PMID: 37994105), though the variant allele fraction mostly suggests somatic origin or artifact (unconfirmed). No relevant functional data are available for this specific missense variant, but in vitro studies have demonstrated that Ser424 is a phosphorylation target of CDK/Cyclin complexes (PMID: 18003885). The computational predictor REVEL gives a score of 0.465, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing, suggesting it 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 (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4.
Met criteria codes
BP4
REVEL score = 0.465, 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
BA1
- Completely absent from gnomAD v2 with a mean coverage of at least 20X. - gnomAD (v3): ALL: 0.005515% (8/145058) - EAS: 0.07016% (4/4276) - FIN: 0.03169% (3/9468) - SAS: 0.002501% (1/4114) - AFR: 0.002501% (1/39980) - gnomAD (v4): ALL: 0.5200% (5949/1143942) - EAS: 2.641% (624/23626) - ASJ: 1.677% (363/21644) - RMG: 1.152% (488/42352) - MEAS: 0.9204% (43/4672) - NFE: 0.4675% (3866/826876) - AFR: 0.4474% (283/63252) - AMR: 0.3607% (164/45462) - FIN: 0.1528% (58/37956) - SAS: 0.07769% (60/77232) *Genomes failed a quality filter (AS_VQSR) in gnomAD v3 and v4. *Allele balance is skewed in gnomAD v2 and v3 and site quality metric may be lower than other common (variant seems to be in a GC-rich region), pathogenic variants.
BS2
Not applicable
BS4
A patient reportedly with hereditary thrombocytopenia and hematological cancer predisposition associated with RUNX1 carried this variant in the germline, but an unspecified number of affected relatives in the family were negative (ClinVar Accession: SCV002515682.3).
BS3
In vitro functional data demonstrated that S424 is a phosphorylation target of CDK/Cyclin complexes (PMID: 18003885).
BS1
- Completely absent from gnomAD v2 with a mean coverage of at least 20X. - gnomAD (v3): ALL: 0.005515% (8/145058) - EAS: 0.07016% (4/4276) - FIN: 0.03169% (3/9468) - SAS: 0.002501% (1/4114) - AFR: 0.002501% (1/39980) - gnomAD (v4): ALL: 0.5200% (5949/1143942) - EAS: 2.641% (624/23626) - ASJ: 1.677% (363/21644) - RMG: 1.152% (488/42352) - MEAS: 0.9204% (43/4672) - NFE: 0.4675% (3866/826876) - AFR: 0.4474% (283/63252) - AMR: 0.3607% (164/45462) - FIN: 0.1528% (58/37956) - SAS: 0.07769% (60/77232) *Genomes failed a quality filter (AS_VQSR) in gnomAD v3 and v4. *Allele balance is skewed in gnomAD v2 and v3 and site quality metric may be lower than other common (variant seems to be in a GC-rich region), pathogenic variants.
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
This rule is not applicable for the MMVCEP
BP2
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches. No homozygotes present in gnomAD v2, v3, or v4.
BP3
Not applicable
BP1
Not applicable
PS4
The variant has been reported in a 59-year-old female with thrombocytopenia and a secondary defect, who also carried RUNX1 c.1256T>G/p.V419G (phasing unclear) and a 2.5 Mb deletion including FLI1, but germline origin was presumed instead of confirmed by tissue or familial testing (PMID: 32935436). One individual in a Japanese family with B-ALL likely due to PAX5 G183R was also found to carry this variant (2 siblings were negative) (PMID: 35902733). Finally, a patient reportedly with hereditary thrombocytopenia and hematological cancer predisposition associated with RUNX1 carried this variant in the germline (ClinVar Accession: SCV002515682.3). The variant of unclear origin has also been reported in patients with AML (PMID: 36900179), MDS (PMID: 36932114), or other tumors (PMID: 30239046; PMID: 30246500; PMID: 32943879; PMID: 35626111; PMID: 37160887; PMID: 37994105), but variant allele fraction mostly suggests somatic origin or artifact (unconfirmed).
PS2
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS3
In vitro functional data demonstrated that S424 is a phosphorylation target of CDK/Cyclin complexes (PMID: 18003885).
PS1
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
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 = 0.465, 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
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
S424A/S397A is the most commonly reported and classified as a VUS by the MM-VCEP. Other S424/S397 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 in a mutational hot spot
PM3
Not applicable
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PM2
- Completely absent from gnomAD v2 with a mean coverage of at least 20X. - gnomAD (v3): ALL: 0.005515% (8/145058) - EAS: 0.07016% (4/4276) - FIN: 0.03169% (3/9468) - SAS: 0.002501% (1/4114) - AFR: 0.002501% (1/39980) - gnomAD (v4): ALL: 0.5200% (5949/1143942) - EAS: 2.641% (624/23626) - ASJ: 1.677% (363/21644) - RMG: 1.152% (488/42352) - MEAS: 0.9204% (43/4672) - NFE: 0.4675% (3866/826876) - AFR: 0.4474% (283/63252) - AMR: 0.3607% (164/45462) - FIN: 0.1528% (58/37956) - SAS: 0.07769% (60/77232) *Genomes failed a quality filter (AS_VQSR) in gnomAD v3 and v4. *Allele balance is skewed in gnomAD v2 and v3 and site quality metric may be lower than other common (variant seems to be in a GC-rich region), pathogenic variants.
Curation History
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