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.649G>A (p.Gly217Arg)

CA10014385

436614 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 25c2ce1c-5117-4f09-bbbe-8ba144738c9c

HGVS expressions

NM_001754.4:c.649G>A

NM_001754.4(RUNX1):c.649G>A (p.Gly217Arg)

NC_000021.9:g.34834566C>T

CM000683.2:g.34834566C>T

NC_000021.8:g.36206863C>T

CM000683.1:g.36206863C>T

NC_000021.7:g.35128733C>T

NG_011402.2:g.1155146G>A

ENST00000675419.1:c.649G>A

ENST00000300305.7:c.649G>A

ENST00000344691.8:c.568G>A

ENST00000358356.9:c.568G>A

ENST00000399237.6:c.613G>A

ENST00000399240.5:c.532+24908G>A

ENST00000437180.5:c.649G>A

ENST00000469087.1:n.185G>A

ENST00000482318.5:c.*239G>A

NM_001001890.2:c.568G>A

NM_001122607.1:c.568G>A

NM_001001890.3:c.568G>A

NM_001122607.2:c.568G>A

NM_001754.5:c.649G>A

NM_001754.5(RUNX1):c.649G>A (p.Gly217Arg)

Uncertain Significance

The Expert Panel has overridden the computationally generated classification - "[unknown]"

PM6 PM2 PM4 PM1 PM5 PM3 PVS1 BS2 BS3 BS4 BS1 BP3 BP2 BP4 BP1 BP7 BP5 PS3 PS1 PS2 PS4 BA1 PP4 PP1 PP3 PP2

Evidence Links 0

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The NM_001754.5(RUNX1):c.649G>A (p.Gly217Arg) variant is reported in gnomAD v3.1 at an MAF of 0.0001064 (0.01%, 7/65790 alleles) in the non-Finish European subpopulation, which does not meet the thresholds for BA1 (≥0.0015) or BS1 (0.00015-0.0015). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PMID: 29365323); however, PS4 cannot be applied as 9 alleles overall are noted in gnomAD. This missense variant has a REVEL score of 0.624, which does not meet the threshold for PP3 (>0.75) or BP4 (<0.15). 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: none.

PM6

No data currently available

PM2

N/A

PM4

N/A

PM1

N/A

PM5

Another variant at the same residue, Gly217Ala, has been curated by the MM-VCEP as VUS. Criteria for PM5 not met.

PM3

MM-VCEP deemed N/A for RUNX1

PVS1

N/A

BS2

MM-VCEP deemed N/A for RUNX1

BS3

No data currently available

BS4

No data currently available

BS1

MAF of 0.0001064 (0.01%; 7/65790 alleles) in the non-Finnish European population of the gnomAD v3.1 cohort does not fall within the 0.00015 (0.015%) and 0.0015 (0.15%) range, and does not meet criteria for BS1

BP3

MM-VCEP deemed N/A for RUNX1

BP2

No data currently available

BP4

This missense variant has a REVEL score of 0.624 and does not meet BP4 cut-off of <0.15. SpliceAI predicts loss of acceptor site of intron 5 with a score of 0.01.

BP1

MM-VCEP deemed N/A for RUNX1

BP7

N/A

BP5

MM-VCEP deemed N/A for RUNX1

PS3

No data currently available

PS1

N/A

PS2

No data currently available

PS4

1 proband from PMID: 29365323, with germ line (cultured fibroblasts) Gly217Arg variant and multiple myeloma and t-AML, with a family history of breast and colon cancers, meets criteria for PS4_Supporting. However, PS4 cannot be applied since 7 alleles are noted in gnomAD non-Finnish European population.

BA1

MAF of 0.0001064 does not meet BA1 threshold

PP4

MM-VCEP deemed N/A for RUNX1

PP1

PMID: 20880108 reports a family with 4 members with thrombocytopenia; however, only the proband was tested for the variant.

PP3

This missense variant has a REVEL score of 0.624 and does not meet PP3 cut-off of >0.75

PP2

MM-VCEP deemed N/A for RUNX1

Approved on: 2021-06-22

Published on: 2022-07-08

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