Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_001754.5(RUNX1):c.486G>T (p.Arg162Ser)

CA16602488

376019 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 4df11a8a-66b6-4bf1-9ad2-b1edf5add537

HGVS expressions

NM_001754.5:c.486G>T
NM_001754.5(RUNX1):c.486G>T (p.Arg162Ser)
NC_000021.9:g.34880579C>A
CM000683.2:g.34880579C>A
NC_000021.8:g.36252876C>A
CM000683.1:g.36252876C>A
NC_000021.7:g.35174746C>A
NG_011402.2:g.1109133G>T
ENST00000675419.1:c.486G>T
ENST00000300305.7:c.486G>T
ENST00000344691.8:c.405G>T
ENST00000358356.9:c.405G>T
ENST00000399237.6:c.450G>T
ENST00000399240.5:c.405G>T
ENST00000437180.5:c.486G>T
ENST00000482318.5:c.*76G>T
NM_001001890.2:c.405G>T
NM_001122607.1:c.405G>T
NM_001754.4:c.486G>T
NM_001001890.3:c.405G>T
NM_001122607.2:c.405G>T

Likely Pathogenic

Met criteria codes 5
PM5_Supporting PS1_Moderate PP3 PM2_Supporting PM1
Not Met criteria codes 21
PS3 PS2 PS4 PP4 PP1 PP2 PVS1 BA1 BS3 BS4 BS1 BS2 PM3 PM4 PM6 BP5 BP7 BP2 BP3 BP4 BP1

Evidence Links 0

Expert Panel

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
NM_001754.5(RUNX1):c.486G>T (p.Arg162Ser) is a missense variant which affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). REVEL score=0.818, which is >0.75 threshold. SSF and MES show loss of a putative cryptic donor splice site at c.485 (PP3). This variant is a missense change at the same residue (p.Arg162) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 376021, 376022) based on MM-VCEP rules for RUNX1 (PM5_Supporting). The c.486G>T variant is the same amino acid change (p.Arg162Ser) as a previously established likely pathogenic variant (ClinVar ID 376020) curated using MM-VCEP rules for RUNX1 (PS1_Moderate). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2_supporting, PM5_supporting, PS1_moderate, PP3.
Met criteria codes
PM5_Supporting
This variant is a missense change at the same residue (p.Arg162) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 376021, 376022) based on MM-VCEP rules for RUNX1 (PM5_Supporting).
PS1_Moderate
The c.486G>T variant is the same amino acid change (p.Arg162Ser) as a previously established likely pathogenic variant (ClinVar ID 376020) curated using MM-VCEP rules for RUNX1 (PS1_Moderate).
PP3
REVEL score=0.818, which is >0.75 threshold. SSF and MES show loss of a putative cryptic donor splice site at c.485 (PP3).
PM2_Supporting
This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).
PM1
This variant affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1).
Not Met criteria codes
PS3
In vitro or in vivo functional data has not been reported for this variant in the literature.
PS2
De novo data for this variant has not been reported in literature.
PS4
While there are reports of this variant in patients with hematological neoplasm, either the cDNA is unknown, germline origin is unknown, or somatic status has been confirmed (PMID: 28855357, 28927163, 31649132, COSMIC).
PP4
This rule is not applicable for MM-VCEP.
PP1
Segregation data for this variant has not been reported in literature.
PP2
This rule is not applicable for MM-VCEP.
PVS1
This variant is not a null variant.
BA1
This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
BS3
In vitro or in vivo functional data has not been reported for this variant in the literature.
BS4
Segregation data for this variant has not been reported in literature.
BS1
This variant does not have a MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental dataset.
BS2
This rule is not applicable for MM-VCEP.
PM3
This rule is not applicable for MM-VCEP.
PM4
This variant is not an in-frame deletion/insertion.
PM6
De novo data for this variant has not been reported in literature.
BP5
This rule is not applicable for MM-VCEP.
BP7
This variant is not a synonymous or intronic variant.
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.
BP3
This rule is not applicable for MM-VCEP.
BP4
This missense variant does not have a REVEL score < 0.50.
BP1
This rule is not applicable for MM-VCEP.
Approved on: 2024-06-24
Published on: 2024-06-24
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