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]

Variant: NM_001754.5(RUNX1):c.1037G>C (p.Arg346Pro)

CA410148448

1999266 (ClinVar)

Gene: RUNX1 (HGNC:861)

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome (MONDO:0011071)

Inheritance Mode: Autosomal dominant inheritance

UUID: fc31d363-ab8a-409b-8047-5e26fb0194c6

Approved on: 2024-08-01

Published on: 2024-08-01

HGVS expressions

NM_001754.5(RUNX1):c.1037G>C (p.Arg346Pro)

NM_001754.5:c.1037G>C

NC_000021.9:g.34792541C>G

CM000683.2:g.34792541C>G

NC_000021.8:g.36164838C>G

CM000683.1:g.36164838C>G

NC_000021.7:g.35086708C>G

NG_011402.2:g.1197171G>C

ENST00000675419.1:c.1037G>C

ENST00000300305.7:c.1037G>C

ENST00000344691.8:c.956G>C

ENST00000399240.5:c.764G>C

ENST00000437180.5:c.1037G>C

ENST00000482318.5:c.*627G>C

NM_001001890.2:c.956G>C

NM_001754.4:c.1037G>C

NM_001001890.3:c.956G>C

Uncertain Significance

PM2_Supporting

PS4 PS2 PS1 BP4 BP1 BP7 BP5 PP3 PP2 BA1 PM6 PM5 PM1 BS1

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.1037G>C (p.Arg346Pro) is a missense variant which is absent from gnomAD v2 and v3 (PM2_Supporting). The computational predictor REVEL gives a score of 0.666, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function, but the splice site predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a VUS 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: PM2_Supporting.

PM2_Supporting

Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).

PS4

No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.

PS2

No literature 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.

BP4

REVEL score = 0.666, 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

BP7

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

BP5

Not applicable

PP3

REVEL score = 0.666, 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

BA1

Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).

PM6

No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.

PM5

Q346/Q319 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.

BS1

Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).

Curation History

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