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.787C>T (p.Pro263Ser)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA10014358

464008 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 6008d288-a114-40c0-b768-5f36eaaecb6c

Approved on: 2025-05-02

Published on: 2025-05-02

HGVS expressions

NM_001754.5:c.787C>T

NM_001754.5(RUNX1):c.787C>T (p.Pro263Ser)

NC_000021.9:g.34834428G>A

CM000683.2:g.34834428G>A

NC_000021.8:g.36206725G>A

CM000683.1:g.36206725G>A

NC_000021.7:g.35128595G>A

NG_011402.2:g.1155284C>T

ENST00000675419.1:c.787C>T

ENST00000300305.7:c.787C>T

ENST00000344691.8:c.706C>T

ENST00000358356.9:c.706C>T

ENST00000399237.6:c.751C>T

ENST00000399240.5:c.532+25046C>T

ENST00000437180.5:c.787C>T

ENST00000469087.1:n.323C>T

ENST00000482318.5:c.*377C>T

NM_001001890.2:c.706C>T

NM_001122607.1:c.706C>T

NM_001754.4:c.787C>T

NM_001001890.3:c.706C>T

NM_001122607.2:c.706C>T

Uncertain Significance

BP4

BS3 BS4 BS1 BS2 BP7 BP5 BP3 BP2 BP1 PS1 PS3 PS2 PS4 PVS1 PP4 PP1 PP3 PP2 PM4 PM5 PM1 PM3 PM6 PM2 BA1

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.787C>T (p.Pro263Ser) is a missense variant which has a REVEL score of 0.286 and a SpliceAI score ≤ 0.20, meeting the threshold for BP4. It is reported at a frequency of 0.0002620 (4/15268 alleles) in the Admixed American population in gnomAD v2.1.1, which does not meet population-based criteria. Although reported in a patient with chronic myelomonocytic leukemia (PMID: 24764152), germline status is not confirmed and other reports concern acquired variants. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4.

BP4

This missense variant has a REVEL score < 0.50 (0.286) and a SpliceAI score ≤ 0.20 (0.03 donor loss) (BP4).

BS3

In vitro or in vivo functional data has not been reported for this variant in the literature.

BS4

No data currently available

BS1

This variant has MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental dataset but is not present in 5 or more alleles (MAF 0.0002620, Admixed American, 4/15268 alleles).

BS2

MM-VCEP deemed N/A for RUNX1

BP7

This variant is not a synonymous or intronic variant.

BP5

MM-VCEP deemed N/A for RUNX1

BP3

MM-VCEP deemed N/A for RUNX1

BP2

No evidence available.

BP1

MM-VCEP deemed N/A for RUNX1

PS1

There has not yet been a different missense change determined to be pathogenic at this amino acid residue.

PS3

In vitro or in vivo functional data has not been reported for this variant in the literature.

PS2

No data currently available

PS4

1 patient from PMID: 24764152 with chronic myelomonocytic leukemia is reported with the Pro263Ser variant at a VAF of 49%. Patient also had variants in SETBP1 and U2AF1. However, information on germ line confirmation is not available. Proband does not meet criteria for PS4.

PVS1

Not a null variant.

PP4

MM-VCEP deemed N/A for RUNX1

PP1

No data currently available

PP3

This missense variant DOES NOT have a REVEL score >0.88 (0.286)

PP2

MM-VCEP deemed N/A for RUNX1

PM4

This variant is not an in-frame deletion/insertion.

PM5

There has not yet been a different missense change determined to be pathogenic at this amino acid residue.

PM1

This variant does not affect any of the following amino acid residues, nor is it located within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 OR within residues 89-204.

PM3

MM-VCEP deemed N/A for RUNX1

PM6

No data currently available

PM2

Variant reported in gnomAD

BA1

This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.

Curation History

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