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]

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

CA16602489

376020 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ab7d4edb-ee0f-46af-8425-b80f572b6ee2

HGVS expressions

NM_001754.5:c.486G>C

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

NC_000021.9:g.34880579C>G

CM000683.2:g.34880579C>G

NC_000021.8:g.36252876C>G

CM000683.1:g.36252876C>G

NC_000021.7:g.35174746C>G

NG_011402.2:g.1109133G>C

ENST00000675419.1:c.486G>C

ENST00000300305.7:c.486G>C

ENST00000344691.8:c.405G>C

ENST00000358356.9:c.405G>C

ENST00000399237.6:c.450G>C

ENST00000399240.5:c.405G>C

ENST00000437180.5:c.486G>C

ENST00000482318.5:c.*76G>C

NM_001001890.2:c.405G>C

NM_001122607.1:c.405G>C

NM_001754.4:c.486G>C

NM_001001890.3:c.405G>C

NM_001122607.2:c.405G>C

Likely Pathogenic

PM5_Supporting PP3 PS1_Moderate PM1 PM2_Supporting

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

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

NM_001754.5(RUNX1):c.486G>C (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 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 376022, 376021) based on MM-VCEP rules for RUNX1 (PM5_Supporting). The c.486G>C variant is the same amino acid change (p.Arg162Ser) as a previously established likely pathogenic variant (ClinVar ID 376019) curated using MM-VCEP rules for RUNX1 (PS1_Moderate). 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 completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_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: PM1, PM5_supporting, PS1_moderate, PM2_supporting, PP3.

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 376022, 376021) based on MM-VCEP rules for RUNX1 (PM5_Supporting).

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.

PS1_Moderate

The c.486G>C variant is the same amino acid change (p.Arg162Ser) as a previously established likely pathogenic variant (ClinVar ID 376019) curated using MM-VCEP rules for RUNX1 (PS1_Moderate).

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).

PM2_Supporting

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).

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: 19357396, 20421268, 21714648, 24030381, 28855357, 28927163, 29057546, 31649132).

PS3

In vitro or in vivo functional data has not been reported for this variant in the literature.

PP4

Not applicable

PP1

Segregation data for this variant has not been reported in literature.

PP2

This rule is not applicable for MM-VCEP.

PM3

Not applicable

PM4

This variant is not an in-frame deletion/insertion.

PM6

De novo data for this variant has not been reported in literature.

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.

BS2

Not applicable

BS4

Segregation data for this variant has not been reported in literature.

BS3

In vitro or in vivo functional data has not been reported for this variant in the literature.

BS1

This variant does not have a MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental dataset.

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

Not applicable

BP4

This missense variant does not have a REVEL score < 0.50.

BP1

This rule is not applicable for MM-VCEP.

BP5

Not applicable

BP7

This variant is not a synonymous or intronic variant.

Approved on: 2024-06-24

Published on: 2024-06-24

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