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_001754.4(RUNX1):c.508+2T>C

CA410202459

642956 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1c4b0383-2515-4886-ac55-0a5bad0dc22a

HGVS expressions

NM_001754.4:c.508+2T>C

NM_001754.4(RUNX1):c.508+2T>C

NC_000021.9:g.34880555A>G

CM000683.2:g.34880555A>G

NC_000021.8:g.36252852A>G

CM000683.1:g.36252852A>G

NC_000021.7:g.35174722A>G

NG_011402.2:g.1109157T>C

NM_001001890.2:c.427+2T>C

NM_001122607.1:c.427+2T>C

NM_001001890.3:c.427+2T>C

NM_001122607.2:c.427+2T>C

ENST00000300305.7:c.508+2T>C

ENST00000344691.8:c.427+2T>C

ENST00000358356.9:c.427+2T>C

ENST00000399237.6:c.472+2T>C

ENST00000399240.5:c.427+2T>C

ENST00000437180.5:c.508+2T>C

ENST00000482318.5:c.*98+2T>C

Likely Pathogenic

PVS1 PM2

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

Evidence Links 2

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The NM_001754.4:c.508+2T>C variant is a donor splice site variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). Two patients reported with this variant in the literature do not meet criteria for PS4 (PMID: 30520015; 29296763). 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.

PVS1

According to the Myeloid Malignancy VCEP rules for RUNX1, the splicing effects table notes that the donor splice site mutations in intron 5 may result in exon 5 skipping with a frameshift or the use of cryptic splice donor site with a frameshift (PMID: 11830488).

PM2

The variant is absent from gnomAD v2.1.1 and gnomAD v3 and meets criteria for PM2.

BS1

Variant meets PM2

BS3

No data currently available

BS4

No data currently available

BP4

N/A

BP2

N/A

BP7

N/A

PS1

N/A

PS3

No data currently available

PS4

Probands from PMIDs: 30520015 and 29296763 are not counted towards PS4 due to multiple mutations and lack of confirmation of germ line origin. From internal laboratory data (SCV000936038.1): Individual in their 40's with thrombocytopenia and family history of hematologic malignancy; however germ line origin was not confirmed. Individual not included for PS4 scoring.

PubMed:29296763

PubMed:30520015

BA1

Variant meets PM2

PP3

N/A

PP1

No data currently available

PM5

N/A

PM4

N/A

PM1

N/A

PM6

No data currently available

Approved on: 2020-03-18

Published on: 2020-06-02

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