Evidence Repository - Clinical Genome Resources

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_001754.5(RUNX1):c.421T>G (p.Ser141Ala)

CA410202644

566052 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: eb6074ef-1f04-4f84-a90b-ec6ec650f2f6

Approved on: 2024-08-12

Published on: 2024-08-12

HGVS expressions

NM_001754.5:c.421T>G

NM_001754.5(RUNX1):c.421T>G (p.Ser141Ala)

NC_000021.9:g.34880644A>C

CM000683.2:g.34880644A>C

NC_000021.8:g.36252941A>C

CM000683.1:g.36252941A>C

NC_000021.7:g.35174811A>C

NG_011402.2:g.1109068T>G

ENST00000675419.1:c.421T>G

ENST00000300305.7:c.421T>G

ENST00000344691.8:c.340T>G

ENST00000358356.9:c.340T>G

ENST00000399237.6:c.385T>G

ENST00000399240.5:c.340T>G

ENST00000437180.5:c.421T>G

ENST00000455571.5:c.382T>G

ENST00000482318.5:c.*11T>G

NM_001001890.2:c.340T>G

NM_001122607.1:c.340T>G

NM_001754.4:c.421T>G

NM_001001890.3:c.340T>G

NM_001122607.2:c.340T>G

Uncertain Significance

PM1_Supporting

PP1 PP4 PP3 PP2 PM5 PM4 PM3 BA1 PM6 PM2 BS2 BS4 BS1 BS3 PS2 PS1 PS3 PS4 BP3 BP2 BP4 BP1 BP5 BP7 PVS1

Evidence Links 0

Expert Panel

Myeloid Malignancy VCEP

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.421T>G (p.Ser141Ala) is a missense variant which has been reported in a mother-son pair with AML (PMID: 32315381 - Supplementary Data/PMID: 28855357 - Supplementary Table 2, and cited by PMID: 32208489 - Supplementary Table 1); however, PS4_supporting cannot be applied because there is >1 allele present in gnomAD (2/282806 alleles in v2 and 2/152176 alleles in v3) and PP1 cannot be applied due to insufficient number of meioses. This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). Biochemical/kinetic studies indicate that this variant has CBFβ-binding comparable to WT, but this assay alone does not meet the requirements for use by the ClinGen Myeloid Malignancy-VCEP. Similarly, the computational predictor REVEL gives a score of 0.851, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function. In summary, this variant meets the criteria to be classified as VUS for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy-VCEP: PM1_supporting.

PM1_Supporting

Not located at a hotspot (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R210, R204), but within residues 89-204.

PP1

The variant has only been reported in a mother-son pair with AML, who also carried CEBPA R297L (PMID: 32315381 - Supplementary Data/PMID: 28855357 - Supplementary Table 2, and cited by PMID: 32208489 - Supplementary Table 1).

PP4

Not applicable

PP3

REVEL score = 0.851, 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

PM5

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM3

Not applicable

BA1

gnomAD (v2): ALL: 0.003911% (2/282806) - NFE: 0.001549% (2/129146) gnomAD (v3): ALL: 0.001314% (2/152176) - AFR: 0.002413% (1/41434) - NFE: 0.001470% (1/68030)

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM2

gnomAD (v2): ALL: 0.003911% (2/282806) - NFE: 0.001549% (2/129146) gnomAD (v3): ALL: 0.001314% (2/152176) - AFR: 0.002413% (1/41434) - NFE: 0.001470% (1/68030)

BS2

Not applicable

BS4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

gnomAD (v2): ALL: 0.003911% (2/282806) - NFE: 0.001549% (2/129146) gnomAD (v3): ALL: 0.001314% (2/152176) - AFR: 0.002413% (1/41434) - NFE: 0.001470% (1/68030)

BS3

Ser141/Ser114 makes contact with N63 and T30 in CBFβ (Table I), but the 15N-1H HSQC spectra of S114A was essentially the same as WT’s runt homology domain (i.e. runt domain fold is unlikely to be perturbed) (Table II). In addition, biochemical/kinetic studies indicate that S114A does not significantly affect CBFβ-binding; more specifically, the K3 (dissociation constant for CBFβ binding to the RD–DNA complex) is ~7.3 which shows a 5.2-fold difference with WT and a much lower fold difference than pathogenic variants (Table III). (PMID: 12807883)

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

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

PS4

The variant was published in a pediatric T-ALL at a VAF=47.7193%, but germline origin is unclear (PMID: 31721781 - Supplementary Table 3). The variant was also detected in a mother-son pair with AML (PMID: 32315381 - Supplementary Data/PMID: 28855357 - Supplementary Table 2, and cited by PMID: 32208489 - Supplementary Table 1), but PS4 cannot be applied because there is >1 allele present in gnomAD. Finally, the variant was observed six times at Invitae, but none of the probands meet the RUNX1-phenotypic criteria.

BP3

Not applicable

BP2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP4

REVEL score = 0.851, which is not less than the v2 threshold of 0.50. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).

BP1

Not applicable

BP5

Not applicable

BP7

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PVS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

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