Variant: NM_001754.5:c.637_638del

CA1139771058

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 28f414d3-a403-43fc-91c7-c2ef9055f497

Approved on: 2024-03-26

Published on: 2024-03-26

HGVS expressions

NM_001754.5:c.637_638del
NC_000021.9:g.34834577_34834578del
CM000683.2:g.34834577_34834578del
NC_000021.8:g.36206874_36206875del
CM000683.1:g.36206874_36206875del
NC_000021.7:g.35128744_35128745del
NG_011402.2:g.1155134_1155135del
ENST00000675419.1:c.637_638del
ENST00000300305.7:c.637_638del
ENST00000344691.8:c.556_557del
ENST00000358356.9:c.556_557del
ENST00000399237.6:c.601_602del
ENST00000399240.5:c.532+24896_532+24897del
ENST00000437180.5:c.637_638del
ENST00000469087.1:n.173_174del
ENST00000482318.5:c.*227_*228del
NM_001001890.2:c.556_557del
NM_001122607.1:c.556_557del
NM_001754.4:c.637_638del
NM_001001890.3:c.556_557del
NM_001122607.2:c.556_557del

Pathogenic

• Met criteria codes: PVS1 PM5_Supporting PM2_Supporting

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

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.637_638del (p.Gln213AspfsTer14) is a frameshift variant which is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (-) c.98-c.758 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting.

Met criteria codes

• PVS1: This variant is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (-) c.98-c.758 as per VCEP specifications) (PVS1).
• PM5_Supporting: This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting).
• PM2_Supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).

Not Met criteria codes

• BA1: This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
• BS2: This rule is not applicable for MM-VCEP.
• BS4: Segregation data for this variant has not been reported in literature.
• BS3: This variant has not been featured in in vitro or in vivo functional studies that show no damaging effect on protein function or splicing.
• BS1: This variant does not have a MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental dataset.
• BP3: This rule is not applicable for MM-VCEP.
• BP2: This variant has not been observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
• BP4: This variant does not have applicable in-silico data available.
• BP1: This rule is not applicable for MM-VCEP.
• BP7: This variant is not a synonymous or intronic variant.
• BP5: This rule is not applicable for MM-VCEP.
• PS2: De novo data for this variant has not been reported in literature.
• PS4: Proband data for this variant has not been reported in literature.
• PS3: This variant has not been featured in in vitro or in vivo functional studies showing a damaging effect on the gene or gene product (Transactivation 25.63% of WT).
• PS1: There has not yet been a missense change determined to be pathogenic at this amino acid residue.
• PP1: Segregation data for this variant has not been reported in literature.
• PP4: This rule is not applicable for MM-VCEP.
• PP3: This variant does not have applicable in-silico data available.
• PP2: This rule is not applicable for MM-VCEP.
• PM6: De novo data for this variant has not been reported in literature.
• PM1: This variant is noThis variant is not a missense variant.t a missense variant.
• PM4: This variant is not an in-frame deletion/insertion.
• PM3: This rule is not applicable for MM-VCEP.