ClinVar Genomic variation as it relates to human health
NM_000314.8(PTEN):c.700C>T (p.Arg234Trp)
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_000314.8(PTEN):c.700C>T (p.Arg234Trp)
Variation ID: 184844 Accession: VCV000184844.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q23.31 10: 87957918 (GRCh38) [ NCBI UCSC ] 10: 89717675 (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 Mar 8, 2017 Feb 20, 2024 Oct 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000314.8:c.700C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000305.3:p.Arg234Trp missense NM_001304717.5:c.1219C>T NP_001291646.4:p.Arg407Trp missense NM_001304718.2:c.109C>T NP_001291647.1:p.Arg37Trp missense NC_000010.11:g.87957918C>T NC_000010.10:g.89717675C>T NG_007466.2:g.99480C>T LRG_311:g.99480C>T LRG_311t1:c.700C>T - Protein change
- R234W, R407W, R37W
- Other names
- NM_000314.6(PTEN):c.700C>T
- Canonical SPDI
- NC_000010.11:87957917:C:T
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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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PTEN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
3002 | 3493 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Nov 18, 2022 | RCV000164170.7 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jul 14, 2015 | RCV000426643.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 27, 2017 | RCV000656997.7 | |
Uncertain significance (2) |
reviewed by expert panel
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Oct 11, 2023 | RCV000790890.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 12, 2018 | RCV001335249.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 15, 2023 | RCV003321527.2 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
(Oct 11, 2023)
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reviewed by expert panel
Method: curation
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PTEN hamartoma tumor syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Clingen PTEN Variant Curation Expert Panel, Clingen
Accession: SCV000930126.2
First in ClinVar: Aug 04, 2019 Last updated: Dec 24, 2023 |
Comment:
NM_000314.8(PTEN):c.700C>T (p.Arg234Trp) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria … (more)
NM_000314.8(PTEN):c.700C>T (p.Arg234Trp) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM2: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. BS3_P: Functional studies showing no damaging effect on protein function. Score of this variant = 0.106334511 (>0, WT-like range) on high throughput phosphatase assay (PMID:29706350). Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign supporting and 2 pathogenic supporting codes get -1 + (1*2) points; total is 1 (Uncertain significance). (less)
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Uncertain significance
(Apr 17, 2015)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000232045.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Sex: mixed
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Uncertain significance
(Dec 27, 2017)
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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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GeneDx
Accession: SCV000565813.5
First in ClinVar: Jul 09, 2018 Last updated: Dec 15, 2018 |
Comment:
This variant is denoted PTEN c.700C>T at the cDNA level, p.Arg234Trp (R234W) at the protein level, and results in the change of an Arginine to … (more)
This variant is denoted PTEN c.700C>T at the cDNA level, p.Arg234Trp (R234W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in leukemia, colorectal, cervical, and vulvar carcinoma samples (Holway 2000, Lin 2015, Spaans 2015, Yuan 2015). PTEN Arg234Trp was not observed in large population cohorts (Lek 2016). PTEN Arg234Trp is located in the C2 domain (Wang 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PTEN Arg234Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(May 30, 2022)
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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: SCV000214788.6
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
The p.R234W variant (also known as c.700C>T), located in coding exon 7 of the PTEN gene, results from a C to T substitution at nucleotide … (more)
The p.R234W variant (also known as c.700C>T), located in coding exon 7 of the PTEN gene, results from a C to T substitution at nucleotide position 700. The arginine at codon 234 is replaced by tryptophan, an amino acid with dissimilar properties. In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally neutral (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Feb 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cowden syndrome 1
Affected status: yes
Allele origin:
paternal
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Baylor Genetics
Accession: SCV001528352.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Uncertain significance
(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: SCV004027108.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
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Uncertain significance
(Nov 18, 2022)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV004357066.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with tryptophan at codon 234 of the PTEN protein. A functional study in a humanized yeast model has shown that … (more)
This missense variant replaces arginine with tryptophan at codon 234 of the PTEN protein. A functional study in a humanized yeast model has shown that this variant results in the loss of phosphatase activity of PTEN protein (PMID: 29706350). This variant has not been reported in individuals affected with PTEN-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Dec 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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PTEN hamartoma tumor syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001226806.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 234 of the PTEN protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 234 of the PTEN protein (p.Arg234Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 184844). 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 PTEN protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PTEN function (PMID: 29706350). 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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Likely pathogenic
(Jul 14, 2015)
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no assertion criteria provided
Method: literature only
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Neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000505650.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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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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A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships. | Mighell TL | American journal of human genetics | 2018 | PMID: 29706350 |
Mutational profiling of colorectal cancers with microsatellite instability. | Lin EI | Oncotarget | 2015 | PMID: 26517354 |
Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
A novel germline mutation of PTEN associated with brain tumours of multiple lineages. | Staal FJ | British journal of cancer | 2002 | PMID: 12085208 |
http://docm.genome.wustl.edu/variants/ENST00000371953:c.700C>T | - | - | - | - |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PTEN | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/45c8d19e-5bfc-4e2d-bc35-187033466d5d | - | - | - | - |
Text-mined citations for rs786201730 ...
HelpRecord last updated Feb 20, 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.