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


Variant: NM_001754.5(RUNX1):c.485G>A (p.Arg162Lys)

CA16602490

376021 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: c20346bb-711e-4d5f-bf45-8f14822fa448
Approved on: 2025-01-15
Published on: 2025-01-15

HGVS expressions

NM_001754.5:c.485G>A
NM_001754.5(RUNX1):c.485G>A (p.Arg162Lys)
NC_000021.9:g.34880580C>T
CM000683.2:g.34880580C>T
NC_000021.8:g.36252877C>T
CM000683.1:g.36252877C>T
NC_000021.7:g.35174747C>T
NG_011402.2:g.1109132G>A
ENST00000675419.1:c.485G>A
ENST00000300305.7:c.485G>A
ENST00000344691.8:c.404G>A
ENST00000358356.9:c.404G>A
ENST00000399237.6:c.449G>A
ENST00000399240.5:c.404G>A
ENST00000437180.5:c.485G>A
ENST00000482318.5:c.*75G>A
NM_001001890.2:c.404G>A
NM_001122607.1:c.404G>A
NM_001754.4:c.485G>A
NM_001001890.3:c.404G>A
NM_001122607.2:c.404G>A
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Uncertain Significance

Met criteria codes 3
PM1 PP3 PM2_Supporting
Not Met criteria codes 23
PM5 PM3 PM4 PS1 PS2 PS4 PS3 BA1 PM6 PP4 PP1 PP2 PVS1 BS4 BS3 BS1 BS2 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

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
NM_001754.5(RUNX1):c.485G>A (p.Arg162Lys) is a missense variant which affects one of the following hotspot residues within the RHD: R162 (PM1). This 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 0.949 (PP3). 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: PM1, PM2_supporting, PP3.
Met criteria codes
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).
PP3
REVEL score=0.949, which is >0.75 threshold. SSF shows loss of a putative cryptic donor splice site at c.485, whereas MES shows a -72.3% score change (just below threshold for significance).
PM2_Supporting
This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).
Not Met criteria codes
PM5
PM1 applied
PM3
Not applicable
PM4
This variant is not an in-frame deletion/insertion.
PS1
There has not yet been a missense change resulting in the same change in protein which has been determined to be pathogenic at this amino acid residue.
PS2
De novo data for this variant has not been reported in literature.
PS4
Invitae tested a proband (70s) with thrombocytopenia and anemia, who didn't have a suggestive family history; however, the variant was not confirmed in the germline. There are published reports of this variant in patients with hematological neoplasm, but either somatic status has been confirmed or germline origin is again unknown (PMID: 19808697, 22689681, 24523240, 24659740, 25592059, 26273060, 27220669, 27534895, 28659335, 28933735, 30373888, 31649132, 32045476, 32208489, COSMIC). Furthermore, R162K has been considered one of the most recurrent somatic missense variants in sporadic AML based on not being observed in a cohort with 103 germline SNV (p<0.05) (PMID: 32208489).
PS3
While there is functional data for this variant (PMID: 25840971; 9533875), it does not meet the thresholds set for even PS3_moderate, which requires reduced transactivation to at least 20% of WT or impact in 2 secondary assays.
BA1
This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
PM6
De novo data for this variant has not been reported in 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.
PVS1
This variant is not a null variant.
BS4
Segregation data for this variant has not been reported in literature.
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 does not have a MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental dataset.
BS2
Not applicable
BP5
Not applicable
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.
Curation History
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