ClinVar Genomic variation as it relates to human health
NM_000314.8(PTEN):c.202T>C (p.Tyr68His)
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.202T>C (p.Tyr68His)
Variation ID: 189474 Accession: VCV000189474.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q23.31 10: 87925550 (GRCh38) [ NCBI UCSC ] 10: 89685307 (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 May 29, 2016 Aug 11, 2024 May 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000314.8:c.202T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000305.3:p.Tyr68His missense NM_000314.6:c.202T>C NM_001304717.5:c.721T>C NP_001291646.4:p.Tyr241His missense NM_001304718.2:c.-541-5496T>C intron variant NC_000010.11:g.87925550T>C NC_000010.10:g.89685307T>C NG_007466.2:g.67112T>C LRG_311:g.67112T>C LRG_311t1:c.202T>C P60484:p.Tyr68His - Protein change
- Y68H, Y241H
- Other names
- p.Y68H:TAC>CAC
- Canonical SPDI
- NC_000010.11:87925549:T:C
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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.
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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 |
3095 | 3599 |
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
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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Pathogenic (1) |
criteria provided, single submitter
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Oct 13, 2023 | RCV000169864.8 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 26, 2023 | RCV000499784.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 2, 2023 | RCV000552740.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 28, 2024 | RCV000491290.7 | |
not provided (1) |
no classification provided
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- | RCV003313047.4 | |
Pathogenic (1) |
criteria provided, single submitter
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May 28, 2023 | RCV003462271.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 24, 2021 | RCV002505225.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 25, 2022 | RCV003231353.4 |
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
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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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Likely pathogenic
(Mar 17, 2016)
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criteria provided, single submitter
Method: clinical testing
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Cowden syndrome 1
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000596622.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
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Pathogenic
(Nov 02, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000645554.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 68 of the PTEN protein (p.Tyr68His). … (more)
This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 68 of the PTEN protein (p.Tyr68His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Cowden syndrome (PMID: 9467011, 9600246, 19457929, 20926450, 25288137, 25669429, 25722288). ClinVar contains an entry for this variant (Variation ID: 189474). 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 expected to disrupt PTEN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302, 19457929, 20926450). This variant disrupts the p.Tyr68 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19457929, 21956414, 24778394, 26246517). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 13, 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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GeneDx
Accession: SCV000222192.14
First in ClinVar: Apr 18, 2015 Last updated: Jul 23, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29970488, 26246517, 19457929, 25669429, 20926450, 9467011, 21659347, 25722288, 11494117, 10400993, 9600246, 24778394, 21956414, 31055886, 29706350, 25288137, 24475377, 30787465, 29152901, 31006514, 36591942, 36453251, 36747841, 32588888, 32127467, 33153119, 29663862, 32665702, 33087929, 37781577, 10866302) (less)
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Likely pathogenic
(May 28, 2024)
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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: SCV000580028.7
First in ClinVar: Jun 25, 2017 Last updated: Aug 11, 2024 |
Comment:
The p.Y68H variant (also known as c.202T>C), located in coding exon 3 of the PTEN gene, results from a T to C substitution at nucleotide … (more)
The p.Y68H variant (also known as c.202T>C), located in coding exon 3 of the PTEN gene, results from a T to C substitution at nucleotide position 202. The tyrosine at codon 68 is replaced by histidine, an amino acid with similar properties. This variant has been identified in individuals meeting clinical diagnostic criteria for Bannayan-Zonana syndrome (BZS) and Cowden syndrome (Marsh DJ. Hum Mol Genet. 1998 Mar;7(3):507-15; Tsou HC et al. Hum. Genet. 1998 Apr;102:467-73; Lobo, GP. Hum Mol Genet. 2009 Aug 1;18(15):2851-62; Cooiman MI et al. Mol Genet Genomic Med. 2019 Jun;7:e00632), and another patient with suspected PTHS (Pilarski, R. J Med Genet. 2011 Aug;48(8):505-12). Functional and structural analyses have demonstrated that this variant produces no phosphatase activity and impairs PTEN protein function, localization and stability (Georgescu MM et al. Cancer Res. 2000 Dec;60:7033-8; Han SY et al. Cancer Res. 2000 Jun;60:3147-51; Lobo, GP. Hum Mol Genet. 2009 Aug 1;18(15):2851-62; He X. Hum Mol Genet. 2011 Jan 1;20(1):80-9; Matreyek KA et al. Nat. Genet. 2018 06;50:874-882; Smith IN et al. J. Biomol. Struct. Dyn. 2019 Apr;37:1766-1782; Smith IN et al. Am. J. Hum. Genet. 2019 May;104:861-878; Mighell TL et al. Am J Hum Genet. 2018 05;102:943-955). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Aug 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cowden syndrome 1
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579459.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4, PM5, PM2_SUP, PP3
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Number of individuals with the variant: 1
Sex: female
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Likely pathogenic
(Nov 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cowden syndrome 1
Familial prostate cancer Macrocephaly-autism syndrome Familial meningioma Glioma susceptibility 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002816215.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Macrocephaly-autism syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
maternal
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV003929452.1
First in ClinVar: Jun 10, 2023 Last updated: Jun 10, 2023 |
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Pathogenic
(Oct 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Macrocephaly-autism syndrome
Affected status: yes
Allele origin:
germline
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Eurofins-Biomnis
Accession: SCV003935061.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
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Likely pathogenic
(Sep 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cowden syndrome 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004188733.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9467011, 9600246, 20926450]. Functional … (more)
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9467011, 9600246, 20926450]. Functional studies indicate this variant impacts protein function [PMID: 10866302]. (less)
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Pathogenic
(May 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glioma susceptibility 2
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004206686.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Cowden syndrome 1
Macrocephaly-autism syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Brain Gene Registry
Accession: SCV004012831.1
First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023 |
Comment:
Variant interpreted as Pathogenic and reported on 01-13-2021 by Lab Prevention Genetics. Assertions are reported exactly as they appear on the patient provided laboratory report. … (more)
Variant interpreted as Pathogenic and reported on 01-13-2021 by Lab Prevention Genetics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less)
Clinical Features:
Phenotypic abnormality (present)
Age: 0-9 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: PreventionGenetics, part of Exact Sciences
Date variant was reported to submitter: 2021-01-13
Testing laboratory interpretation: Pathogenic
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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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Conformational Dynamics and Allosteric Regulation Landscapes of Germline PTEN Mutations Associated with Autism Compared to Those Associated with Cancer. | Smith IN | American journal of human genetics | 2019 | PMID: 31006514 |
Dynamics and structural stability effects of germline PTEN mutations associated with cancer versus autism phenotypes. | Smith IN | Journal of biomolecular structure & dynamics | 2019 | PMID: 29663862 |
Genetic obesity: next-generation sequencing results of 1230 patients with obesity. | Kleinendorst L | Journal of medical genetics | 2018 | PMID: 29970488 |
Multiplex assessment of protein variant abundance by massively parallel sequencing. | Matreyek KA | Nature genetics | 2018 | PMID: 29785012 |
A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships. | Mighell TL | American journal of human genetics | 2018 | PMID: 29706350 |
Cowden's syndrome with immunodeficiency. | Browning MJ | Journal of medical genetics | 2015 | PMID: 26246517 |
PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. | Jansen LA | Brain : a journal of neurology | 2015 | PMID: 25722288 |
KLLN epigenotype-phenotype associations in Cowden syndrome. | Nizialek EA | European journal of human genetics : EJHG | 2015 | PMID: 25669429 |
Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism. | Frazier TW | Molecular psychiatry | 2015 | PMID: 25288137 |
Second malignant neoplasms in patients with Cowden syndrome with underlying germline PTEN mutations. | Ngeow J | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2014 | PMID: 24778394 |
Incidence and clinical characteristics of thyroid cancer in prospective series of individuals with Cowden and Cowden-like syndrome characterized by germline PTEN, SDH, or KLLN alterations. | Ngeow J | The Journal of clinical endocrinology and metabolism | 2011 | PMID: 21956414 |
Naturally occurring germline and tumor-associated mutations within the ATP-binding motifs of PTEN lead to oxidative damage of DNA associated with decreased nuclear p53. | He X | Human molecular genetics | 2011 | PMID: 20926450 |
Germline and somatic cancer-associated mutations in the ATP-binding motifs of PTEN influence its subcellular localization and tumor suppressive function. | Lobo GP | Human molecular genetics | 2009 | PMID: 19457929 |
Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor. | Georgescu MM | Cancer research | 2000 | PMID: 11156408 |
Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay. | Han SY | Cancer research | 2000 | PMID: 10866302 |
The genetic basis of Cowden's syndrome: three novel mutations in PTEN/MMAC1/TEP1. | Tsou HC | Human genetics | 1998 | PMID: 9600246 |
Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. | Marsh DJ | Human molecular genetics | 1998 | PMID: 9467011 |
- | - | - | - | DOI: 10.1515/jpem-2012-0227 |
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Text-mined citations for rs398123317 ...
HelpRecord last updated Sep 29, 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.