Variant: NM_001754.5(RUNX1):c.590_597del (p.Val197fs)

CA2580098634

1706546 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 94e47b7b-d0c6-4c13-aab2-cf61701bdceb

HGVS expressions

NM_001754.5:c.590_597del
NM_001754.5(RUNX1):c.590_597del (p.Val197fs)
NC_000021.9:g.34859491_34859498del
CM000683.2:g.34859491_34859498del
NC_000021.8:g.36231788_36231795del
CM000683.1:g.36231788_36231795del
NC_000021.7:g.35153658_35153665del
NG_011402.2:g.1130215_1130222del
ENST00000675419.1:c.590_597del
ENST00000300305.7:c.590_597del
ENST00000344691.8:c.509_516del
ENST00000358356.9:c.509_516del
ENST00000399237.6:c.554_561del
ENST00000399240.5:c.509_516del
ENST00000437180.5:c.590_597del
ENST00000467577.1:n.82_89del
ENST00000482318.5:c.*180_*187del
NM_001001890.2:c.509_516del
NM_001122607.1:c.509_516del
NM_001754.4:c.590_597del
NM_001001890.3:c.509_516del
NM_001122607.2:c.509_516del

Pathogenic

• Met criteria codes: PM5_Supporting PM2_Supporting

• Not Met criteria codes: PM1 PM4 PVS1 PM6 BA1 BS4 BS3 BS1 BP7 BP2 BP4 PS2 PS3 PS1 PP1 PP3

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 NM_001754.5(RUNX1):c.590_597del change is a frameshift variant that is predicted to introduce a premature stop codon and is expected to result in nonsense-mediated mRNA decay. This variant is predicted to affect all the biologically relevant transcripts (PVS1). In addition, this is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting), and it affects AA downstream of c.98 (in transcript NM_001754.4) (PM5_supporting). Although, this has been found in a single patient in a large cohort of AML cases (PMID: 27137476), its allele frequency and/or germinal origin is unknown. Therefore, we cannot assess case-study/segregation criteria. In summary, this variant meets the 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, and PM5_supporting.

Met criteria codes

• PM5_Supporting: This is a frameshift variant affecting AA downstream of c.98 (in transcript NM_001754.4) (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

• PM1: This rule cannot be applied since this is not a missense variant.
• PM4: This rule cannot be applied since this is a frameshift variant.
• PVS1: This is a frameshift variant that is predicted to undergo nonsense mediated decay. However, this variant is not located within any biologically relevant transcripts.
• PM6: To our knowledge, this variant has been found in a single patient in a single study (PMID: 27137476). However, we have no information about its germinal origin and segregation in the family. Therefore, this rule cannot be applied.
• BA1: This variant is completely absent from all population databases with at least 20x coverage for RUNX1.
• BS4: To our knowledge, this variant has been found in a single patient in a single study (PMID: 27137476). However, we have no information about its germinal origin and segregation in the family. Therefore, this rule cannot be applied.
• BS3: This rule cannot be applied since no functional studies have been reported.
• BS1: This variant is completely absent from all population databases with at least 20x coverage for RUNX1.
• BP7: This rule cannot be applied since this is a frameshift variant.
• BP2: To our knowledge, this variant has been found in a single patient in a single study (PMID: 27137476). However, we have no information about the haplotype of the patient. Therefore, this rule cannot be applied.
• BP4: This rule cannot be applied since this is a frameshift variant.
• PS2: To our knowledge, this variant has been found in a single patient in a single study (PMID: 27137476). However, we have no information about its germinal origin and segregation in the family. Therefore, this rule cannot be applied.
• PS3: This rule cannot be applied since no functional studies have been reported.
• PS1: This rule cannot be applied since this is a frameshift variant.
• PP1: To our knowledge, this variant has been found in a single patient in a single study (PMID: 27137476). However, we have no information about its germinal origin and segregation in the family. Therefore, this rule cannot be applied.
• PP3: This rule cannot be applied since this is a frameshift variant.

Approved on: 2023-12-09

Published on: 2023-12-09