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]
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Variant: NM_001754.5(RUNX1):c.270dup (p.Arg91fs)

CA1139666850

988416 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 1cb2af09-f5cf-4a19-a62f-b3ba138de38b

HGVS expressions

NM_001754.5:c.270dup
NM_001754.5(RUNX1):c.270dup (p.Arg91fs)
NC_000021.9:g.34886924dup
CM000683.2:g.34886924dup
NC_000021.8:g.36259221dup
CM000683.1:g.36259221dup
NC_000021.7:g.35181091dup
NG_011402.2:g.1102788dup
ENST00000675419.1:c.270dup
ENST00000300305.7:c.270dup
ENST00000344691.8:c.189dup
ENST00000358356.9:c.189dup
ENST00000399237.6:c.234dup
ENST00000399240.5:c.189dup
ENST00000437180.5:c.270dup
ENST00000455571.5:c.231dup
ENST00000482318.5:c.59-6211dup
NM_001001890.2:c.189dup
NM_001122607.1:c.189dup
NM_001754.4:c.270dup
NM_001001890.3:c.189dup
NM_001122607.2:c.189dup

Pathogenic

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

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 NM_001754.5(RUNX1):c.270dup (p.Arg91AlafsTer47) variant in RUNX1 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 5/9 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2, v3, and v4 with at least 20x coverage (PM2_Supporting). The variant has been reported in a 78yo female with AML, but variant origin is unclear (PMID: 37680325); it has also been reported in 1/3219 patients referred for clinical diagnostic testing who underwent WGS, but phenotype and germline origin are unspecified (PMID: 33726816) (PS4_Supporting is not met). However, other pathogenic/likely pathogenic frameshift alterations in exons 4 or 5 have been reported (PMID: 35764482) (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant 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. (Version 2; date of approval)
Met criteria codes
PVS1
Frameshift deletion resulting in a premature stop codon in exon 5, which is expected to result in a product subject to nonsense-mediated decay.
PM5_Supporting
Other pathogenic or likely pathogenic frameshift alterations in exon 4 (coding exon 3) and/or with a premature truncation codon in exon 5 have been reported (Feurstein et al., 2022, 35764482 - Supplementary Table 5).
PM2_Supporting
Completely absent from gnomAD with a mean coverage of at least 20X (v2+v3+v4).
Not Met criteria codes
PS4
The variant has been reported in a 78yo female with AML, but variant origin is unclear (PMID: 37680325); it has also been reported in 1/3219 patients referred for clinical diagnostic testing who underwent WGS, but phenotype and germline origin are unspecified (PMID: 33726816).
PS2
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS3
No relevant literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
Not a synonymous or intronic variant
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
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+v3+v4).
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.
BS2
Not applicable
BS4
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS3
No relevant literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS1
Completely absent from gnomAD with a mean coverage of at least 20X (v2+v3+v4).
Approved on: 2023-12-09
Published on: 2023-12-09
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