VCV000380212.37 - ClinVar

NM_006231.4(POLE):c.3156G>A (p.Thr1052=)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(13)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006231.4(POLE):c.3156G>A (p.Thr1052=)

Variation ID: 380212 Accession: VCV000380212.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.33 12: 132659414 (GRCh38) [ NCBI UCSC ] 12: 133236000 (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	Jul 1, 2017	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006231.4:c.3156G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006222.2:p.Thr1052=	synonymous
NC_000012.12:g.132659414C>T
NC_000012.11:g.133236000C>T
NG_033840.1:g.33111G>A
LRG_789:g.33111G>A
LRG_789t1:c.3156G>A	LRG_789p1:p.Thr1052=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000012.12:132659413:C:T

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.

0.39457 (C)

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

Exome Aggregation Consortium (ExAC) 0.50285

The Genome Aggregation Database (gnomAD), exomes 0.50336

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.52245

The Genome Aggregation Database (gnomAD) 0.53577

Trans-Omics for Precision Medicine (TOPMed) 0.55142

1000 Genomes Project 0.60543

1000 Genomes Project 30x 0.61071

Links

ClinGen: CA6893345 dbSNP: rs5744857 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.
POLE		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	9159	9372

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.
not specified	Benign (5)	criteria provided, multiple submitters, no conflicts	Oct 17, 2016	RCV000421896.21
Hereditary cancer-predisposing syndrome	Benign (1)	criteria provided, single submitter	May 20, 2015	RCV000492265.11
not provided	Benign (4)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000588598.21
Colorectal cancer, susceptibility to, 12	Benign (1)	criteria provided, multiple submitters, no conflicts	Jul 7, 2023	RCV001520943.14
Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency	Benign (1)	criteria provided, single submitter	Oct 25, 2021	RCV001789331.10
Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	Benign (1)	criteria provided, single submitter	Oct 25, 2021	RCV001789330.10

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.
Benign (Aug 17, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698670.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (2) PubMed: 20091185‚ 21129811 Comment: Variant summary: The POLE c.3156G>A (p.Thr1052Thr) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a … (more) Variant summary: The POLE c.3156G>A (p.Thr1052Thr) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 9827/18014 control chromosomes at a frequency of 0.5455202 (with numerous hozomygotes occurrence), which significantly exceeds the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. This variant has been reported in patients and classified by authors as polymorphism. Taken together, this variant is classified as benign. (less)
Benign (Oct 30, 2015)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000517995.4 First in ClinVar: Mar 08, 2017 Last updated: Apr 09, 2018	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Oct 17, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000806758.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (Mar 29, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000711960.2 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Comment: Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency Number of individuals with the variant: 1
Benign (May 20, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000581372.6 First in ClinVar: Jul 01, 2017 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (Oct 25, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Facial dysmorphism-immunodeficiency-livedo-short stature syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002031650.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021
Benign (Oct 25, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002031651.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021
Benign (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer, susceptibility to, 12 Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004016680.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001730163.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 14, 2024
Benign (Nov 30, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001473381.7 First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005237242.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001925552.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001957922.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

Variant summary: The POLE c.3156G>A (p.Thr1052Thr) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 9827/18014 control chromosomes at a frequency of 0.5455202 (with numerous hozomygotes occurrence), which significantly exceeds the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. This variant has been reported in patients and classified by authors as polymorphism. Taken together, this variant is classified as benign.

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
Associations between polymorphisms in DNA repair genes and TP53 mutations in non-small cell lung cancer.	Cho S	Lung cancer (Amsterdam, Netherlands)	2011	PMID: 21129811
MGMT -535G>T polymorphism is associated with prognosis for patients with metastatic colorectal cancer treated with oxaliplatin-based chemotherapy.	Park JH	Journal of cancer research and clinical oncology	2010	PMID: 20091185

Text-mined citations for rs5744857 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_006231.4(POLE):c.3156G>A (p.Thr1052=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs5744857 ...