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.991A>C (p.Ser331Arg)

CA410148750

1023243 (ClinVar)

Gene: RUNX1 (HGNC:861)

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

Inheritance Mode: Autosomal dominant inheritance

UUID: 246d841c-9c31-4705-9ec3-f81fb633152d

Approved on: 2024-08-12

Published on: 2024-08-12

HGVS expressions

NM_001754.5(RUNX1):c.991A>C (p.Ser331Arg)

NM_001754.5:c.991A>C

NC_000021.9:g.34792587T>G

CM000683.2:g.34792587T>G

NC_000021.8:g.36164884T>G

CM000683.1:g.36164884T>G

NC_000021.7:g.35086754T>G

NG_011402.2:g.1197125A>C

ENST00000675419.1:c.991A>C

ENST00000300305.7:c.991A>C

ENST00000344691.8:c.910A>C

ENST00000399240.5:c.718A>C

ENST00000437180.5:c.991A>C

ENST00000482318.5:c.*581A>C

NM_001001890.2:c.910A>C

NM_001754.4:c.991A>C

NM_001001890.3:c.910A>C

Uncertain Significance

BP4 PM2_Supporting

PS2 PS3 PS4 PS1 BP1 BP2 BP3 BP5 BP7 PP3 PP2 PP1 PP4 BA1 PM6 PM1 PM3 PM4 PM5 BS2 BS4 BS3 BS1 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.991A>C (p.Ser331Arg) is a missense variant which is absent from gnomAD v2 and v3 (PM2_Supporting). The computational predictor REVEL gives a score of 0.106, and the splice site predictor SpliceAI indicated 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 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 and BP4.

BP4

REVEL score = 0.106, which is less than the v2 threshold of 0.50. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).

PM2_Supporting

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

PS2

No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.

PS3

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

PS4

No relevant cases found in literature search, including 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.

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

PP3

REVEL score = 0.106, 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

PP1

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

PP4

Not applicable

BA1

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

PM6

No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.

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

PM5

S331N/S304R has been reported in Mastermind, but not frequently enough to suggest pathogenicity.

BS2

Not applicable

BS4

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

BS3

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

BS1

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

PVS1

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

Curation History

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