ClinVar Genomic variation as it relates to human health
NM_006231.4(POLE):c.1420G>A (p.Val474Ile)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006231.4(POLE):c.1420G>A (p.Val474Ile)
Variation ID: 235886 Accession: VCV000235886.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.33 12: 132673217 (GRCh38) [ NCBI UCSC ] 12: 133249803 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Feb 25, 2017 May 1, 2024 Jan 10, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006231.4:c.1420G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006222.2:p.Val474Ile missense NC_000012.12:g.132673217C>T NC_000012.11:g.133249803C>T NG_033840.1:g.19308G>A LRG_789:g.19308G>A LRG_789t1:c.1420G>A LRG_789p1:p.Val474Ile - Protein change
- V474I
- Other names
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- Canonical SPDI
- NC_000012.12:132673216:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- variation affecting protein function Variation Ontology [VariO:0003]
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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POLE | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
9003 | 9213 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Apr 19, 2023 | RCV000417197.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 19, 2023 | RCV001011505.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 10, 2024 | RCV003539821.1 |
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
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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
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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. |
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Uncertain significance
(Apr 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, susceptibility to, 12
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004018526.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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Uncertain significance
(Mar 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, susceptibility to, 12
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000786198.2
First in ClinVar: Feb 25, 2017 Last updated: Feb 25, 2017 |
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Uncertain significance
(Jan 10, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000943380.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 474 of the POLE protein (p.Val474Ile). … (more)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 474 of the POLE protein (p.Val474Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28423643). ClinVar contains an entry for this variant (Variation ID: 235886). 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 POLE protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects POLE function (PMID: 28423643). 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)
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Uncertain significance
(Oct 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001171832.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.V474I variant (also known as c.1420G>A), located in coding exon 14 of the POLE gene, results from a G to A substitution at nucleotide … (more)
The p.V474I variant (also known as c.1420G>A), located in coding exon 14 of the POLE gene, results from a G to A substitution at nucleotide position 1420. The valine at codon 474 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in an early-onset colorectal cancer patient from a family meeting Amsterdam I criteria without alterations in the mismatch repair system (Esteban-Jurado C et al. Oncotarget, 2017 Apr;8:26732-26743). Further, a functional analysis by Esteban-Jurado et al. using a yeast-based model showed this alteration resulted in an increased mutation rate due to faulty proofreading activity as compared to wild-type, but was still milder than the previously reported mutation p.Leu424Val. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Pathogenic
(May 25, 2016)
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no assertion criteria provided
Method: research
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Colorectal cancer, susceptibility to, 12
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Genetic Predisposition to Colorectal Cancer Group, Institut d’Investigacions Biomediques August Pi i Sunyer
Accession: SCV000268710.1
First in ClinVar: Feb 25, 2017 Last updated: Feb 25, 2017 |
Comment:
The POLE c.1420G>A (p.Val474Ile) variant was not present in any of the accessed human genetic variation databases including a Spanish repository (dbSNP, 1000Genomes, Exome Variant … (more)
The POLE c.1420G>A (p.Val474Ile) variant was not present in any of the accessed human genetic variation databases including a Spanish repository (dbSNP, 1000Genomes, Exome Variant Server, Exome Aggregation Consortium and CIBERER Spanish variant server). The affected amino acid is conserved in 100 vertebrates as well as in D. melanogaster, C. elegans and yeast, and it is very close to the C terminus end of the exonuclease domain (3 amino acids away). Analysis of the POLE structure showed that the variant may not affect DNA binding directly but it could have an indirect effect on the helical packing of the exonuclease and N-terminal domains, which could distort the physiological conformation needed for a correct polymerase activity. Also, bioinformatics tools (PolyPhen and CADD) predicted a deleterious effect for this amino acid change and protein stability predictions were also in favor of a damaging effect. Functional studies on S. pombe concluded that the mutation rate of this variant was 31 times higher when compared to the wild-type strain (P-value <0.005) but milder than the previously reported p.Leu424Val. (less)
Indication for testing: Early-onset colorectal cancer
Age: 40-49 years
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: Catalonia
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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variation affecting protein function
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Genetic Predisposition to Colorectal Cancer Group, Institut d’Investigacions Biomediques August Pi i Sunyer
Accession: SCV000268710.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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POLE and POLD1 screening in 155 patients with multiple polyps and early-onset colorectal cancer. | Esteban-Jurado C | Oncotarget | 2017 | PMID: 28423643 |
Text-mined citations for rs980578884 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.