ClinVar Genomic variation as it relates to human health
NM_006231.4(POLE):c.16G>C (p.Gly6Arg)
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.
Uncertain significance(2); Benign(5); Likely benign(10)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006231.4(POLE):c.16G>C (p.Gly6Arg)
Variation ID: 218680 Accession: VCV000218680.57
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.33 12: 132687300 (GRCh38) [ NCBI UCSC ] 12: 133263886 (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 Dec 27, 2015 May 1, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006231.4:c.16G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006222.2:p.Gly6Arg missense NC_000012.12:g.132687300C>G NC_000012.11:g.133263886C>G NG_033840.1:g.5225G>C LRG_789:g.5225G>C LRG_789t1:c.16G>C LRG_789p1:p.Gly6Arg - Protein change
- G6R
- Other names
- -
- Canonical SPDI
- NC_000012.12:132687299:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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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0.00180 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00161
1000 Genomes Project 30x 0.00172
1000 Genomes Project 0.00180
Exome Aggregation Consortium (ExAC) 0.00195
The Genome Aggregation Database (gnomAD) 0.00293
Trans-Omics for Precision Medicine (TOPMed) 0.00370
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 | ||
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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
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. |
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POLE | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
9003 | 9213 | |
LOC130009266 | - | - | - | GRCh38 | - | 186 |
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. |
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Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000202795.17 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 1, 2015 | RCV000210904.5 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Dec 31, 2019 | RCV000233156.19 | |
Conflicting interpretations of pathogenicity (10) |
criteria provided, conflicting classifications
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Feb 1, 2024 | RCV000432993.37 | |
Benign (3) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2020 | RCV000568177.6 | |
Benign (1) |
no assertion criteria provided
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- | RCV001355562.4 |
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. |
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Likely benign
(Jul 22, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000258038.2
First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015 |
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Likely benign
(Nov 01, 2015)
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criteria provided, single submitter
Method: research
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Colorectal cancer
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: CSER - NEXT Medicine variant annotation
Accession: SCV000264609.1 First in ClinVar: Apr 23, 2016 Last updated: Apr 23, 2016
Comment:
Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 41 year old female with a diagnosis … (more)
Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 41 year old female with a diagnosis of uterine cancer. Variant is not in exonuclease domain. .GERP=2.51.ExAC Alt Allele Frequencies=AFR:0.311%,NFE:0.676%,EAS:0.0%,SAS:0.027%,FIN:unknown,AMR:0.0%,OTH:0.0%. (less)
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Uncertain Significance
(Nov 10, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511481.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Converted during submission to Uncertain significance.
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Likely benign
(Dec 07, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000518043.4
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)
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Likely benign
(Feb 20, 2017)
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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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PreventionGenetics, part of Exact Sciences
Accession: SCV000806726.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
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Benign
(Aug 05, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698662.2
First in ClinVar: Mar 08, 2017 Last updated: Nov 10, 2019 |
Comment:
Variant summary: POLE c.16G>C (p.Gly6Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: POLE c.16G>C (p.Gly6Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 110214 control chromosomes, predominantly at a frequency of 0.0045 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 317 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.16G>C has been reported in the literature in individuals affected with Colorectal Cancer (ex Kothari_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Nine of these ten have classified the variant as benign (n=3)/likely benign (n=6). Based on the evidence outlined above, the variant was re-evaluated as benign. (less)
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Likely benign
(Jul 06, 2016)
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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: SCV000488841.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
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Benign
(Apr 17, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889712.3
First in ClinVar: Sep 13, 2018 Last updated: Dec 31, 2022 |
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Benign
(Feb 01, 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: SCV000289265.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
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Likely benign
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001148917.21
First in ClinVar: Feb 03, 2020 Last updated: Apr 15, 2024 |
Comment:
POLE: BS1
Number of individuals with the variant: 9
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Benign
(Nov 06, 2019)
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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: SCV000671367.5
First in ClinVar: Jan 01, 2018 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)
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Likely benign
(Oct 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002071627.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Benign
(Jul 31, 2020)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002536763.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Dec 31, 2019)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, susceptibility to, 12
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761454.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009605.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Likely benign
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002550233.4
First in ClinVar: Jul 27, 2022 Last updated: Aug 18, 2023 |
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Likely benign
(Oct 25, 2023)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004562143.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
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Likely benign
(Dec 01, 2017)
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no assertion criteria provided
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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True Health Diagnostics
Accession: SCV000788161.1
First in ClinVar: Jan 01, 2018 Last updated: Jan 01, 2018 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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Carcinoma of colon
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550484.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The POLE p.Gly6Arg variant was not identified in the literature nor was it identified in the MutDB database. The variant was identified in the following … (more)
The POLE p.Gly6Arg variant was not identified in the literature nor was it identified in the MutDB database. The variant was identified in the following databases: dbSNP (ID: rs202220778) as “With other allele”, ClinVar and Clinvitae (9x as benign by Invitae and Ambry Genetics, as likely benign by Children's Hospital of Philadelphia, University of Washington Medical Center, Counsyl, GeneDx, Quest Diagnostics, Integrated Genetics, and as uncertain significance by Center for Pediatric Genomic Medicine). The variant was identified in control databases in 353 of 136976 chromosomes (2 homozygous) at a frequency of 0.0025 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African in 13 of 11652 chromosomes (freq: 0.0011), “Other” in 11 of 3924 chromosomes (freq: 0.003), Latino in 51 of 21270 chromosomes (freq: 0.002), European Non-Finnish in 220 of 52786 chromosomes (freq: 0.004), Ashkenazi Jewish in 44 of 7670 chromosomes (freq: 0.006), European Finnish in 10 of 11688 chromosomes (freq: 0.00085), and South Asian in 4 of 19714 chromosomes (freq: 0.000203). While the variant was not observed in the East Asian, populations. The p.Gly6Arg residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. (less)
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001799699.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807904.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001917162.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971563.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Increased incidence of FBXW7 and POLE proofreading domain mutations in young adult colorectal cancers. | Kothari N | Cancer | 2016 | PMID: 27244218 |
Text-mined citations for rs202220778 ...
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.