Evidence Repository
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.489dup (p.Val164fs)

CA2579914604

1704949 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8aca650c-b3c8-4369-afa1-f0e7b9338ea3

HGVS expressions

NM_001754.5:c.489dup
NM_001754.5(RUNX1):c.489dup (p.Val164fs)
NC_000021.9:g.34880578dup
CM000683.2:g.34880578dup
NC_000021.8:g.36252875dup
CM000683.1:g.36252875dup
NC_000021.7:g.35174745dup
NG_011402.2:g.1109136dup
ENST00000675419.1:c.489dup
ENST00000300305.7:c.489dup
ENST00000344691.8:c.408dup
ENST00000358356.9:c.408dup
ENST00000399237.6:c.453dup
ENST00000399240.5:c.408dup
ENST00000437180.5:c.489dup
ENST00000482318.5:c.*79dup
NM_001001890.2:c.408dup
NM_001122607.1:c.408dup
NM_001754.4:c.489dup
NM_001001890.3:c.408dup
NM_001122607.2:c.408dup

Pathogenic

Met criteria codes 3
PM5_Supporting PVS1 PM2_Supporting
Not Met criteria codes 23
PS3 PS2 PS4 PS1 PP1 PP4 PP3 PP2 BA1 BS3 BS4 BS1 BS2 PM1 PM3 PM4 PM6 BP7 BP5 BP2 BP3 BP4 BP1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
The c.489dup (p.Val164Cysfs*49) variant in RUNX1 is a frameshift duplication predicted to cause a premature stop codon in biologically-relevant exon 7/9 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent from gnomAD v2 and v3 with a mean coverage of at least 20X (PM2_Supporting). It has also been described in a 67yo male with AML who had a daughter with AML at age 21 (HSCT at age 26), and an additional daughter and 2 sons with thrombocytopenia, but germline origin was not confirmed (PMID: 32804409, cited by PMID: 35884491) (PS4_Supporting does not apply). Regardless, there are 25 nonsense/frameshift variants classified as pathogenic by the MM-VCEP in exons 3-7 (two per exon) with sufficient molecular and specific clinical data (PMID: 35764482) (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1, PM2_Supporting, and PM5_Supporting.
Met criteria codes
PM5_Supporting
There are 25 nonsense/frameshift variants classified as pathogenic by the MM-VCEP in exons 3-7 (two per exon) without use of PM5_Supporting (PMID: 35764482).
PVS1
The c.489dup (p.Val164Cysfs*49) variant in RUNX1 is a frameshift duplication predicted to cause a premature stop codon in biologically-relevant exon 7/9 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism.
PM2_Supporting
Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).
Not Met criteria codes
PS3
No relevant literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS2
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS4
The variant of unclear origin was detected in a 67yo male with AML who had a daughter with AML at age 21 (HSCT at age 26), and an additional daughter and 2 sons with thrombocytopenia (PMID: 32804409, cited by PMID: 35884491).
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PP4
Not applicable
PP3
SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
PP2
Not applicable
BA1
Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).
BS3
No relevant literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS4
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS1
Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).
BS2
Not applicable
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
Not applicable
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
Not applicable
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
Not applicable
BP4
SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
BP1
Not applicable
Approved on: 2023-11-13
Published on: 2023-11-13
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