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.35C>T (p.Ser12Leu)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA410208238

532661 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 9896b77f-1016-403c-8943-abece94e9495

Approved on: 2025-05-02

Published on: 2025-05-02

HGVS expressions

NM_001754.5:c.35C>T

NM_001754.5(RUNX1):c.35C>T (p.Ser12Leu)

NC_000021.9:g.35048865G>A

CM000683.2:g.35048865G>A

NC_000021.8:g.36421162G>A

CM000683.1:g.36421162G>A

NC_000021.7:g.35343032G>A

NG_011402.2:g.940847C>T

ENST00000675419.1:c.35C>T

ENST00000300305.7:c.35C>T

ENST00000416754.1:c.35C>T

ENST00000437180.5:c.35C>T

ENST00000455571.5:c.35C>T

ENST00000475045.6:c.35C>T

ENST00000482318.5:c.35C>T

NM_001754.4:c.35C>T

Likely Benign

BS1 BP4

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

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.35C>T (p.Ser12Leu) is a missense variant which has a MAF of 0.001644 (0.01644%, 1/6084 alleles) in the Middle Eastern subpopulation of the gnomAD v4.1.0 cohort, meeting the threshold for BS1. This variant has a REVEL score < 0.50 (0.305) and a SpliceAI score ≤ 0.20 (0.06) (BP4). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4.

BS1

MAF of 0.001644 (0.01644%, 1/6084 alleles) in the Middle Eastern subpopulation of the gnomAD v4.1.0 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1).

BP4

This missense variant has a REVEL score < 0.50 (0.305) and a SpliceAI score ≤ 0.20 (acceptor loss of 0.06) (BP4).

PP1

No segregation data has been identified.

PP4

This rule is not applicable for MM-VCEP.

PP3

This missense variant has a REVEL score < 0.50 (0.305) and a SpliceAI score ≤ 0.20 (acceptor loss of 0.06)

PP2

This rule is not applicable for MM-VCEP.

PM1

This missense variant is not located in a hotspot residue established by the MM-VCEP.

PM5

No different missense change identified.

PM3

This rule is not applicable for MM-VCEP.

PM4

This missense variant is not predicted to affect splicing. There is no evidence of protein length changes.

PM6

No published de novo cases.

PM2

This variant is present in at least one population database.

PVS1

This missense variant with no predicted impact on splice site.

BS2

This rule is not applicable for MM-VCEP.

BS4

No segregation data has been identified.

BS3

No previous functional studies identified for this variant.

BP2

No co-existing pathogenic variant known.

BP3

This rule is not applicable for MM-VCEP.

BP1

This rule is not applicable for MM-VCEP.

BP7

This is a missense variant and does not meet BP7 criteria.

BP5

This rule is not applicable for MM-VCEP.

PS2

No published de novo cases.

PS4

This variant has been reported in one proband meeting at least one of the RUNX1-phenotype criteria (PS4_Supporting; PMID: 34166225). However, according to RUNX1 protocol guidelines, PS4_XXXX cannot be applied because the variant presents more than 2 times (X) in gnomAD. This variant is present 14 times in gnomAD v4.1.0. This variant also present in a cohort of head and neck cancer ( PMID: 27442865) Therefore, the previous PS4_supporting criteria is removed.

PS3

No previous functional studies identified for this variant.

PS1

This amino acid change has not been previously established.

Curation History

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.