Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_001754.4(RUNX1):c.488T>G (p.Phe163Cys)

CA410202504

575111 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: c2db7d34-2a30-4083-8012-4bfee19ca22b

HGVS expressions

NM_001754.4:c.488T>G

NM_001754.4(RUNX1):c.488T>G (p.Phe163Cys)

NC_000021.9:g.34880577A>C

CM000683.2:g.34880577A>C

NC_000021.8:g.36252874A>C

CM000683.1:g.36252874A>C

NC_000021.7:g.35174744A>C

NG_011402.2:g.1109135T>G

ENST00000675419.1:c.488T>G

ENST00000300305.7:c.488T>G

ENST00000344691.8:c.407T>G

ENST00000358356.9:c.407T>G

ENST00000399237.6:c.452T>G

ENST00000399240.5:c.407T>G

ENST00000437180.5:c.488T>G

ENST00000482318.5:c.*78T>G

NM_001001890.2:c.407T>G

NM_001122607.1:c.407T>G

NM_001001890.3:c.407T>G

NM_001122607.2:c.407T>G

NM_001754.5:c.488T>G

NM_001754.5(RUNX1):c.488T>G (p.Phe163Cys)

Uncertain Significance

PP3 PM1_Supporting PM2_Supporting

PS3 PS2 PS4 PS1 PP4 PP1 PP2 PM4 PM3 PM5 PM6 PVS1 BA1 BS2 BS3 BS4 BS1 BP3 BP2 BP4 BP1 BP7 BP5

Evidence Links 0

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The c.488T>G (p.Phe163Cys) variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score of ≥0.88 (0.986) (PP3). The variant occurs at residue 163 located in the RHD, which is determined to be a critical functional domain by MM-VCEP (PM1_Supporting). The variant has not been reported in patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_Supporting.

PP3

Variant meets PP3 with REVEL score of 0.986 (threshold >0.75)

PM1_Supporting

The variant occurs at residue 163 located in the RHD, which is determined to be a critical functional domain by MM-VCEP, meeting PM1_Supporting.

PM2_Supporting

Phe163Cys is absent from gnomAD v2 and v3 at >20x coverage

PS3

No data currently available

PS2

No data currently available

PS4

The variant has not been reported in patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge.

PS1

N/A

PP4

MM-VCEP deemed N/A for RUNX1

PP1

No data currently available

PP2

MM-VCEP deemed N/A for RUNX1

PM4

N/A

PM3

MM-VCEP deemed N/A for RUNX1

PM5

Phe163Leu is a variant at the same residue provisionally classified as VUS by the MM-VCEP. PM5 is not considered here to avoid circularity.

PM6

No data currently available

PVS1

N/A

BA1

Variant meets PM2

BS2

MM-VCEP deemed N/A for RUNX1

BS3

No data currently available

BS4

No data currently available

BS1

Variant meets PM2

BP3

MM-VCEP deemed N/A for RUNX1

BP2

No data currently available

BP4

Variant meets PP3

BP1

MM-VCEP deemed N/A for RUNX1

BP7

N/A

BP5

MM-VCEP deemed N/A for RUNX1

Approved on: 2022-07-08

Published on: 2022-07-08

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