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

UUID: 8aca650c-b3c8-4369-afa1-f0e7b9338ea3

Approved on: 2023-11-13

Published on: 2023-11-13

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: PVS1 PM5_Supporting PM2_Supporting

• Not Met criteria codes: BP2 BP3 BP4 BP1 BP7 BP5 PS3 PS2 PS4 PS1 PM1 PM3 PM4 PM6 BA1 PP1 PP4 PP3 PP2 BS2 BS3 BS4 BS1

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

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

• 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.
• 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).
• PM2_Supporting: Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).

Not Met criteria codes

• 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
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: Not applicable
• 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
• 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.
• BA1: Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).
• 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
• BS2: Not applicable
• 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).