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]

Link to SEPIO compliant JSON-LD document

Variant: NM_001754.5(RUNX1):c.296G>A (p.Cys99Tyr)

CA410203612

1321699 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b1b1314c-2b74-4b29-b48c-eed1873b71ba

Approved on: 2024-07-17

Published on: 2024-07-17

HGVS expressions

NM_001754.5:c.296G>A

NM_001754.5(RUNX1):c.296G>A (p.Cys99Tyr)

NC_000021.9:g.34886898C>T

CM000683.2:g.34886898C>T

NC_000021.8:g.36259195C>T

CM000683.1:g.36259195C>T

NC_000021.7:g.35181065C>T

NG_011402.2:g.1102814G>A

ENST00000675419.1:c.296G>A

ENST00000300305.7:c.296G>A

ENST00000344691.8:c.215G>A

ENST00000358356.9:c.215G>A

ENST00000399237.6:c.260G>A

ENST00000399240.5:c.215G>A

ENST00000437180.5:c.296G>A

ENST00000455571.5:c.257G>A

ENST00000482318.5:c.59-6185G>A

NM_001001890.2:c.215G>A

NM_001122607.1:c.215G>A

NM_001754.4:c.296G>A

NM_001001890.3:c.215G>A

NM_001122607.2:c.215G>A

Uncertain Significance

PS4_Moderate PM1_Supporting PP3 PM2_Supporting

BA1 BP7 BP5 BP2 BP3 BP4 BP1 BS4 BS3 BS1 BS2 PP1 PP4 PP2 PS2 PS3 PS1 PM5 PM3 PM4 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.296G>A (p.Cys99Tyr) is a missense variant that impacts one of the residues within the runt homology domain, but not a known hotspot residue (PM1_supporting). This variant has a REVEL score >0.88 (0.963) (PP3) and is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). It has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 30291338, PMID: 36436542). Additionally, this variant was reported in ClinVar in 2021 by GeneDx, but the affected status of the proband is unknown (Variation ID 1321699). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting, PS4_Moderate.

PS4_Moderate

This variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 30291338, PMID: 36436542). This variant was reported in Clinvar in 2021 by GeneDx but the affected status of the proband is unknown (Variation ID 1321699).

PM1_Supporting

This variant affects one of the other residues (AA 89-204) within the RHD (PM1_Supporting).

PP3

This missense variant has a REVEL score >0.88 (0.963) (PP3).

PM2_Supporting

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

BA1

This rule is not met because this variant is completely absent from all population databases.

BP7

This rule is not met because this is a missense variant.

BP5

This rule is not applicable for MM-VCEP.

BP2

This rule is not applicable because the variant is completely absent from all population databases.

BP3

This rule is not applicable for MM-VCEP.

BP4

This rule is not met because this missense variant does not have a REVEL score<0.50 (0.963).

BP1

This rule is not applicable for MM-VCEP.

BS4

This rule is not met because there is no data available on this variant in affected members of family.

BS3

This rule is not met because there are no reported functional assays for this variant.

BS1

This rule is not met because this variant is completely absent from all population databases.

BS2

This rule is not applicable for MM-VCEP.

PP1

This rule is not met because there is no data available on this variant in affected members of family.

PP4

This rule is not applicable for MM-VCEP.

PP2

This rule is not applicable for MM-VCEP.

PS2

This rule is not applicable because there is no information on affected individuals nor the family.

PS3

This rule is not met because there are no reported functional assays for this variant.

PS1

This rule is not met because there are no previously established pathogenic variants with the same amino acid change as this variant that were curated using MM-VCEP rules for RUNX1.

PM5

This rule is not applicable because this variant is the only variant found in this codon.

PM3

This rule is not applicable for MM-VCEP.

PM4

This rule is not met because this is a missense variant.

PVS1

This rule is not met because this is a missense variant.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.