VCV000464008.14 - ClinVar

NM_001754.5(RUNX1):c.787C>T (p.Pro263Ser)

Germline

Top reviewed classifications are shown here.

Submission summary:

7 submissions

7 submitters

5 conditions

Reviewed by expert panel

Uncertain significance

Jul 2022 by ClinGen Myeloi… FDA Recognized Database

for Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001754.5(RUNX1):c.787C>T (p.Pro263Ser)

Variation ID: 464008 Accession: VCV000464008.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 21q22.12 21: 34834428 (GRCh38) [ NCBI UCSC ] 21: 36206725 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 10, 2018	Oct 13, 2024	Jul 8, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001754.5:c.787C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001745.2:p.Pro263Ser	missense
NM_001001890.3:c.706C>T	NP_001001890.1:p.Pro236Ser	missense
NM_001122607.2:c.706C>T	NP_001116079.1:p.Pro236Ser	missense
NC_000021.9:g.34834428G>A
NC_000021.8:g.36206725G>A
NG_011402.2:g.1155284C>T
LRG_482:g.1155284C>T
LRG_482t1:c.787C>T	LRG_482p1:p.Pro263Ser

... more HGVS ... less HGVS

Protein change

P263S, P236S

Other names

NM_001754.4(RUNX1):c.787C>T
p.Pro263Ser

Canonical SPDI

NC_000021.9:34834427:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00005

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Links

ClinGen: CA10014358 dbSNP: rs370315332 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RUNX1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1265	1627

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Mar 26, 2024	RCV000528679.9
Acute myeloid leukemia Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	Uncertain significance (1)	criteria provided, single submitter	May 24, 2022	RCV000765504.3
Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	Uncertain significance (1)	reviewed by expert panel	Jul 8, 2022	RCV002264713.1
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Apr 7, 2024	RCV003129891.4
Acute myeloid leukemia	Uncertain significance (1)	criteria provided, single submitter	Sep 19, 2023	RCV003470746.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jul 08, 2022)	reviewed by expert panel (ClinGen MyeloMalig ACMG Specifications v2) Method: curation	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Myeloid Malignancy Variant Curation Expert Panel FDA Recognized Database Accession: SCV002546390.1 First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6008d288-a114-40c0-b768-5f36eaaecb6c Comment: The NM_001754.5(RUNX1):c.787C>T (p.Pro263Ser) variant is reported at a frequency of 0.00004476 (0.004%, 5/111718 alleles) in the non-Finnish European population of gnomAD v2.1.1 cohort which does … (more) The NM_001754.5(RUNX1):c.787C>T (p.Pro263Ser) variant is reported at a frequency of 0.00004476 (0.004%, 5/111718 alleles) in the non-Finnish European population of gnomAD v2.1.1 cohort which does not fall within 0.00015 (0.015%) and 0.0015 (0.15%) range, thus not meeting BS1 criteria. 1 patient from PMID: 24764152 with chronic myelomonocytic leukemia is reported with the Pro263Ser variant at a VAF of 49%. Patient also had variants in SETBP1 and U2AF1. However, information on germ line confirmation is not available. Proband does not meet criteria for PS4. This missense variant has a REVEL score 0.286, which does not meet criteria for PP3 or BP4. 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: none. (less)
Uncertain significance (May 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Acute myeloid leukemia Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000896807.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000638158.6 First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 263 of the RUNX1 protein (p.Pro263Ser). … (more) This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 263 of the RUNX1 protein (p.Pro263Ser). This variant is present in population databases (rs370315332, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 464008). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RUNX1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Sep 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acute myeloid leukemia Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004209845.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (Oct 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003814340.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806570.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Uncertain significance (Apr 07, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005372207.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as a pathogenic or benign germline variant … (more) In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 24764152, 37754227) (less)

Comment:

The NM_001754.5(RUNX1):c.787C>T (p.Pro263Ser) variant is reported at a frequency of 0.00004476 (0.004%, 5/111718 alleles) in the non-Finnish European population of gnomAD v2.1.1 cohort which does not fall within 0.00015 (0.015%) and 0.0015 (0.15%) range, thus not meeting BS1 criteria. 1 patient from PMID: 24764152 with chronic myelomonocytic leukemia is reported with the Pro263Ser variant at a VAF of 49%. Patient also had variants in SETBP1 and U2AF1. However, information on germ line confirmation is not available. Proband does not meet criteria for PS4. This missense variant has a REVEL score 0.286, which does not meet criteria for PP3 or BP4. 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: none.

Comment:

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 263 of the RUNX1 protein (p.Pro263Ser). This variant is present in population databases (rs370315332, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 464008). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RUNX1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 24764152, 37754227)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6008d288-a114-40c0-b768-5f36eaaecb6c	-	-	-	-

Text-mined citations for rs370315332 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001754.5(RUNX1):c.787C>T (p.Pro263Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs370315332 ...