Variant: NM_001754.5(RUNX1):c.296G>A (p.Cys99Tyr)

CA410203612

1321699 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: b1b1314c-2b74-4b29-b48c-eed1873b71ba

Approved on: 2024-07-17

Published on: 2024-07-17

HGVS expressions

NM_001754.5:c.296G>A
NM_001754.5(RUNX1):c.296G>A (p.Cys99Tyr)
NC_000021.9:g.34886898C>T
CM000683.2:g.34886898C>T
NC_000021.8:g.36259195C>T
CM000683.1:g.36259195C>T
NC_000021.7:g.35181065C>T
NG_011402.2:g.1102814G>A
ENST00000675419.1:c.296G>A
ENST00000300305.7:c.296G>A
ENST00000344691.8:c.215G>A
ENST00000358356.9:c.215G>A
ENST00000399237.6:c.260G>A
ENST00000399240.5:c.215G>A
ENST00000437180.5:c.296G>A
ENST00000455571.5:c.257G>A
ENST00000482318.5:c.59-6185G>A
NM_001001890.2:c.215G>A
NM_001122607.1:c.215G>A
NM_001754.4:c.296G>A
NM_001001890.3:c.215G>A
NM_001122607.2:c.215G>A

Uncertain Significance

• Met criteria codes: PP3 PS4_Moderate PM2_Supporting PM1_Supporting

• Not Met criteria codes: PS2 PS3 PS1 BA1 PP1 PP4 PP2 PM5 PM3 PM4 BS4 BS3 BS1 BS2 BP7 BP5 BP2 BP3 BP4 BP1 PVS1

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

NM_001754.5(RUNX1):c.296G>A (p.Cys99Tyr) is a missense variant that impacts one of the residues within the runt homology domain, but not a known hotspot residue (PM1_supporting). This variant has a REVEL score >0.88 (0.963) (PP3) and is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). It has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 30291338, PMID: 36436542). Additionally, this variant was reported in ClinVar in 2021 by GeneDx, but the affected status of the proband is unknown (Variation ID 1321699). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting, PS4_Moderate.

Met criteria codes

• PP3: This missense variant has a REVEL score >0.88 (0.963) (PP3).
• PS4_Moderate: This variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 30291338, PMID: 36436542). This variant was reported in Clinvar in 2021 by GeneDx but the affected status of the proband is unknown (Variation ID 1321699).
• PM2_Supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting).
• PM1_Supporting: This variant affects one of the other residues (AA 89-204) within the RHD (PM1_Supporting).

Not Met criteria codes

• PS2: This rule is not applicable because there is no information on affected individuals nor the family.
• PS3: This rule is not met because there are no reported functional assays for this variant.
• PS1: This rule is not met because there are no previously established pathogenic variants with the same amino acid change as this variant that were curated using MM-VCEP rules for RUNX1.
• BA1: This rule is not met because this variant is completely absent from all population databases.
• PP1: This rule is not met because there is no data available on this variant in affected members of family.
• PP4: This rule is not applicable for MM-VCEP.
• PP2: This rule is not applicable for MM-VCEP.
• PM5: This rule is not applicable because this variant is the only variant found in this codon.
• PM3: This rule is not applicable for MM-VCEP.
• PM4: This rule is not met because this is a missense variant.
• BS4: This rule is not met because there is no data available on this variant in affected members of family.
• BS3: This rule is not met because there are no reported functional assays for this variant.
• BS1: This rule is not met because this variant is completely absent from all population databases.
• BS2: This rule is not applicable for MM-VCEP.
• BP7: This rule is not met because this is a missense variant.
• BP5: This rule is not applicable for MM-VCEP.
• BP2: This rule is not applicable because the variant is completely absent from all population databases.
• BP3: This rule is not applicable for MM-VCEP.
• BP4: This rule is not met because this missense variant does not have a REVEL score<0.50 (0.963).
• BP1: This rule is not applicable for MM-VCEP.
• PVS1: This rule is not met because this is a missense variant.