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.98-2A>G

CA410204329

2011850 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e279e16d-ca92-42ec-8a4b-6c54a7529b26

Approved on: 2023-12-09

Published on: 2023-12-09

HGVS expressions

NM_001754.5:c.98-2A>G

NM_001754.5(RUNX1):c.98-2A>G

NC_000021.9:g.34887098T>C

CM000683.2:g.34887098T>C

NC_000021.8:g.36259395T>C

CM000683.1:g.36259395T>C

NC_000021.7:g.35181265T>C

NG_011402.2:g.1102614A>G

ENST00000675419.1:c.98-2A>G

ENST00000300305.7:c.98-2A>G

ENST00000344691.8:c.15A>G

ENST00000358356.9:c.15A>G

ENST00000399237.6:c.62-2A>G

ENST00000399240.5:c.15A>G

ENST00000437180.5:c.98-2A>G

ENST00000455571.5:c.59-2A>G

ENST00000475045.6:c.98-2A>G

ENST00000482318.5:c.59-6385A>G

NM_001001890.2:c.15A>G

NM_001122607.1:c.15A>G

NM_001754.4:c.98-2A>G

NM_001001890.3:c.15A>G

NM_001122607.2:c.15A>G

Likely Pathogenic

PM2_Supporting PVS1

PM6 PM1 PM4 PM5 BA1 BS4 BS3 BS1 PS2 PS4 PS3 PS1 BP7 BP2 BP4 PP1 PP3

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The c.98-2A>G is a canonical splice site variant that is predicted to disrupt exon 4 acceptor splice site recognition (SpliceAI prediction: acceptor loss 0.75, at -2 bp), introduce exon 4 skipping, and produce a frameshift with a premature stop codon, resulting in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases (gnomAD v2.1 and v3.1) with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in three probands (PMID: 27288520, 29932212, and 36436542). They were diagnosed with myelodysplastic syndromes (one case) or acute myeloid leukemia (two cases). However, the germinal origin of the variant cannot be confirmed in any of them. In addition, another variant, the c.98-1G>A change, was discovered in a family with a patient who was diagnosed with an inherited platelet disorder. This latter has an impact on the same acceptor splice site and is likely to have the same effects on splicing (PMID: 32935436). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting.

PM2_Supporting

This variant is completely absent from all population databases (gnomAD v2.1.1 and v3.1.2) with at least 20x coverage for RUNX1 (PM2_supporting).

PVS1

PM6

This rule cannot be applied since, to our knowledge, this variant has not been reported in any study.

PM1

This rule cannot be applied since this is a canonical splice site variant.

PM4

This rule cannot be applied since this is a canonical splice site variant that is predicted to disrupt exon 4 acceptor splice site recognition, introduce exon 4 skipping, and produce a frameshift with a premature stop codon, resulting in nonsense-mediated mRNA decay.

PM5

This rule cannot be applied since this is a canonical splice site variant.

BA1

This rule cannot be applied since the variant is completely absent from all population databases.

BS4

This rule cannot be applied since, to our knowledge, this variant has not been reported in any study and we have no information about segregation.

BS3

To our knowledge, no in vitro or in vivo functional studies are available for this variant.

BS1

This rule cannot be applied since the variant is completely absent from all population databases.

PS2

This rule cannot be applied since, to our knowledge, this variant has not been reported in any study.

PS4

This variant has been reported in three probands (PMID: 27288520, 29932212, and 36436542). They were diagnosed with myelodysplastic syndromes (one case) or acute myeloid leukemia (two cases). However, the germinal origin of the variant cannot be confirmed in any of them. In addition, the c.98-1G>A variant was found in a family with a patient who was diagnosed with an inherited platelet disorder. This variant affects the same acceptor splice site and would probably result in the same aberrant splicing (PMID: 32935436).

PS3

To our knowledge, no in vitro or in vivo functional studies are available for this variant. In addition, PS3 cannot be applied because the variant meets PVS1

PS1

This rule cannot be applied since this is a canonical splice site variant.

BP7

This rule cannot be applied since this is a canonical splice site variant.

BP2

This rule cannot be applied since, to our knowledge, this variant has not been reported in any study.

BP4

This rule cannot be applied since this is a canonical splice site variant.

PP1

This rule cannot be applied since, to our knowledge, this variant has not been reported in any study and we have no information about its cosegregation with the disease.

PP3

This rule cannot be applied since this is a canonical splice site variant.

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