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.508+1G>A

CA410202463

812739 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5760cc2c-55d6-459b-83ab-8074e87a3409

HGVS expressions

NM_001754.5:c.508+1G>A

NM_001754.5(RUNX1):c.508+1G>A

NC_000021.9:g.34880556C>T

CM000683.2:g.34880556C>T

NC_000021.8:g.36252853C>T

CM000683.1:g.36252853C>T

NC_000021.7:g.35174723C>T

NG_011402.2:g.1109156G>A

ENST00000675419.1:c.508+1G>A

ENST00000300305.7:c.508+1G>A

ENST00000344691.8:c.427+1G>A

ENST00000358356.9:c.427+1G>A

ENST00000399237.6:c.472+1G>A

ENST00000399240.5:c.427+1G>A

ENST00000437180.5:c.508+1G>A

ENST00000482318.5:c.*98+1G>A

NM_001001890.2:c.427+1G>A

NM_001122607.1:c.427+1G>A

NM_001754.4:c.508+1G>A

NM_001001890.3:c.427+1G>A

NM_001122607.2:c.427+1G>A

Pathogenic

PS4_Moderate PVS1 PM2_Supporting

PS3 PS1 PS2 PP4 PP1 PP3 PP2 BA1 BS3 BS1 BS4 BS2 PM1 PM5 PM4 PM3 PM6 BP5 BP7 BP3 BP2 BP4 BP1

Evidence Links 0

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The c.508+1G>A variant has not been reported in gnomAD (v2 and v3) (PM2_supporting) or in case reports. It is predicted to result in the use of a cryptic site 23nt upstream of 5' splice site. This is predicted to lead to a frameshift and a premature termination codon leading to loss of function to the protein. SpliceAI delta score =1. (PVS1). This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 29632235, SCV001161868.1, 2 (Patient ID :A001099, A001100) PMID: 29632235). This variant was found to co-segregate with disease in affected family members, with two meioses observed in one family (PMID: 29632235). The maternal grandmother and great uncle had history of AML but have not been screened for the RUNX1 variant so cannot be included. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4_Moderate, PM2_Supporting.

PS4_Moderate

This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID:32581362, SCV001161868.1, 2 (Patient ID :A001099, A001100) and PMID: 29632235).

PVS1

The c.508+1G>A variant is predicted to result in the use of a cryptic site 23 nt upstream of 5' splice site. This is predicted to lead to a frameshift and a premature termination codon leading to loss of function to the protein. SpliceAI delta score =1. PMID: 11830488

PM2_Supporting

This variant is completely absent from all population databases with at least 20x coverage for RUNX1

PS3

literature search conducted and evidence supporting functional studies is not found at this given time

PS1

Frameshift variant

PS2

This variant has not been reported in probands in the literature.

PP4

This rule is not applicable for MM-VCEP

PP1

This variant was found to co-segregate with disease in affected family members, with two (2) meioses observed in one family (PMID: 29632235). The maternal grandmother and great uncle had history of AML but have not been screened for the RUNX1 variant so cannot be included.

PP3

Not a missense variant therefore no REVEL Score was found and SpliceAI score 1.00 for donor loss and 0.54 for donor gain which is both ≥ 0.38

PP2

This rule is not applicable for MM-VCEP

BA1

This variant is completely absent from all population databases with at least 20x coverage for RUNX1

BS3

literature search conducted and evidence supporting functional studies is not found at this given time

BS1

This variant is completely absent from all population databases with at least 20x coverage for RUNX1

BS4

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

BS2

This rule is not applicable for MM-VCEP

PM1

This variant does not affect one of the hotspot residues established by the MM-VCEP for RUNX1

PM5

Not a missense variant

PM4

This is a splicing variant and PM4 is only applied for in-frame deletion/insertion variants therefore this rule would not apply.

PM3

This rule is not applicable for MM-VCEP

PM6

This variant has not been reported in probands in the literature.

BP5

This rule is not applicable for MM-VCEP

BP7

Not a synonymous variant

BP3

This rule is not applicable for MM-VCEP

BP2

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 therefore no homozygotes present in gnomAD

BP4

Not a missense variant therefore no REVEL Score was found and SpliceAI score 1.00 for donor loss and 0.54 for donor gain which is not ≤ 0.20

BP1

This rule is not applicable for MM-VCEP

Approved on: 2022-08-31

Published on: 2023-11-13

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