Variant: NC_000021.8:g.35304341_36865875del

812913 (ClinVar)

Gene: N/A

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 2f4c000b-53a7-47a5-8e41-ec944ba3654a

HGVS expressions

NC_000021.8:g.35304341_36865875del

Pathogenic

• Met criteria codes: PM2_Supporting PM5_Supporting PVS1 PS4_Supporting

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

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Myeloid Malignancy VCEP

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 32581362). 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 likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS4_supporting, PM5_supporting.

Met criteria codes

• PM2_Supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1
• PM5_Supporting: This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting).
• PVS1: This variant is a frameshift variant resulting in exon deletion (PVS1).
• PS4_Supporting: This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 32581362)

Not Met criteria codes

• PM6: PM6 cannot be applied because this variant only has one proband.
• PM1: This variant is located in a non-coding region
• PM4: Protein length does not change as a result of this deletion.
• PM3: This rule is not applicable for MM-VCEP
• BS2: This rule is not applicable for MM-VCEP
• BS4: This variant has not been reported in affected family members.
• 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 is completely absent from all population databases with at least 20x coverage for RUNX1
• BP4: REVEL data only returned for missense/single nucleotide variants.
• BP1: This rule is not applicable for MM-VCEP
• 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.
• BP7: This is not a synonymous variant.
• BP5: This rule is not applicable for MM-VCEP
• PS2: 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.
• PS3: This variant has not been featured in in vitro or in vivo functional studies that show no damaging effect on protein function or splicing.
• PS1: This variant does not have a missense change.
• BA1: This variant is completely absent from all population databases with at least 20x coverage for RUNX1
• PP1: This variant was not found to co-segregate with disease in multiple affected family members.
• PP3: REVEL data only returned for missense/single nucleotide variants.
• PP2: This rule is not applicable for MM-VCEP
• PP4: This rule is not applicable for MM-VCEP

Approved on: 2023-12-09

Published on: 2023-12-09