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]

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

CA16602490

376021 (ClinVar)

Gene: RUNX1 (HGNC:861)

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome (MONDO:0011071)

Inheritance Mode: Autosomal dominant inheritance

UUID: c20346bb-711e-4d5f-bf45-8f14822fa448

Approved on: 2026-04-29

Published on: 2026-04-29

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

Likely Pathogenic

PM1_Strong PM2_Supporting PP3

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

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 for RUNX1 Version 3.1.0

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 hotspot residues (R162) in the RHD (PM1_strong). This variant has a REVEL score ≥ 0.88 (0.949) (PP3) and a MAF ≤ 0.00005 in gnomAD v4 across all subpopulations 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_strong, PM2_supporting, PP3.

PM1_Strong

This variant affects the following hotspot residue within the RHD: R162 (PM1_strong).

PM2_Supporting

This variant has a MAF ≤ 0.00005 in gnomAD v4.0 in all subpopulations with at least 20X coverage for RUNX1 (PM2_supporting).

PP3

This missense variant has a REVEL score ≥ 0.88 (0.949) (PP3).

PVS1

This variant is not a null variant.

BS2

Not applicable

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.

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.

BP5

Not applicable

BP7

This variant is not a synonymous or intronic variant.

BA1

This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.

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.

PP4

Not applicable

PP1

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

PP2

This rule is not applicable for MM-VCEP.

PM5

PM1 applied

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.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.