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_001754.5(RUNX1):c.952T>C (p.Ser318Pro)

CA320255462

1000131 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 9f9c67cd-b098-4205-9c3d-2dcff11376fd

Approved on: 2022-07-07

Published on: 2022-07-07

HGVS expressions

NM_001754.5:c.952T>C

NM_001754.5(RUNX1):c.952T>C (p.Ser318Pro)

NC_000021.9:g.34799316A>G

CM000683.2:g.34799316A>G

NC_000021.8:g.36171613A>G

CM000683.1:g.36171613A>G

NC_000021.7:g.35093483A>G

NG_011402.2:g.1190396T>C

ENST00000675419.1:c.952T>C

ENST00000300305.7:c.952T>C

ENST00000344691.8:c.871T>C

ENST00000399240.5:c.679T>C

ENST00000437180.5:c.952T>C

ENST00000482318.5:c.*542T>C

NM_001001890.2:c.871T>C

NM_001754.4:c.952T>C

NM_001001890.3:c.871T>C

Uncertain Significance

BP4

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

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

The c.952T>C (p.Ser318Pro) missense variant has a REVEL score <0.50 (0.188) and SpliceAI does not predict (Δ scores ≤ 0.20) a significant impact on the canonical splice sites or the creation of putative cryptic splice sites (BP4). It has otherwise not been described in the literature. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4.

BP4

REVEL=0.188, which is above the V1 threshold of 0.15 but below the V2 threshold of 0.50. No impact on splicing (existing or putative cryptic splice sites) per SpliceAI.

BA1

gnomAD v2: ALL: 0.00040% - AFR: 0.0062% (1/16256 alleles) gnomAD v3: absent with >20x coverage

BS2

Not applicable

PVS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS3

No publications in HGMD, ClinVar, LOVD, COSMIC, or Google/Google Scholar searches.

BS1

gnomAD v2: ALL: 0.00040% - AFR: 0.0062% (1/16256 alleles) gnomAD v3: absent with >20x coverage

BP5

Not applicable

BP7

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP3

Not applicable

BP1

Not applicable

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS4

No publications in HGMD, ClinVar, LOVD, COSMIC, or Google/Google Scholar searches.

PS3

No publications in HGMD, ClinVar, LOVD, COSMIC, or Google/Google Scholar searches.

PS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP4

Not applicable

PP3

REVEL=0.188, which is below the V1 threshold of 0.75 and the V2 threshold of 0.88.

PP2

Not applicable

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM2

gnomAD v2: ALL: 0.00040% - AFR: 0.0062% (1/16256 alleles) gnomAD v3: absent with >20x coverage

PM1

Not located at a hotspot (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R210, R204) or within residues 89-204.

PM5

S318A has been reported in at least 2 patients who developed AML (23753029-confirmed germline; 28933735:A1-VAF=14.9%, likely somatic), 2 brothers with primary immunodeficiency who also carried LP/P G6PC3 alterations (27577878:E1), and a pediatric Ewing’s sarcoma cell line (25186949:S16). However, this variant is classified as benign by the MM-VCEP.

PM3

Not applicable

PM4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

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.