This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
ClinVar Genomic variation as it relates to human health
NM_000314.8(PTEN):c.633C>A (p.Cys211Ter)
Germline
Classification
Help
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.
(11)
Help
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.
Pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000314.8(PTEN):c.633C>A (p.Cys211Ter)
Variation ID: 7836 Accession: VCV000007836.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q23.31 10: 87952258 (GRCh38) [ NCBI UCSC ] 10: 89712015 (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 Apr 4, 2013 May 1, 2024 Jun 14, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000314.8:c.633C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000305.3:p.Cys211Ter nonsense NM_000314.6:c.633C>A NM_001304717.5:c.1152C>A NP_001291646.4:p.Cys384Ter nonsense NM_001304718.2:c.42C>A NP_001291647.1:p.Cys14Ter nonsense NC_000010.11:g.87952258C>A NC_000010.10:g.89712015C>A NG_007466.2:g.93820C>A LRG_311:g.93820C>A LRG_311t1:c.633C>A - Protein change
- C211*, C14*, C384*
- Other names
- -
- Canonical SPDI
- NC_000010.11:87952257:C:A
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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
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| PTEN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
3098 | 3607 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Sep 1, 2000 | RCV000008284.4 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 5, 2023 | RCV000409569.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 27, 2022 | RCV000490942.3 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 22, 2022 | RCV000820375.8 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 14, 2023 | RCV001269918.8 | |
|
PTEN-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Mar 15, 2023 | RCV004528092.1 |
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
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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|---|---|---|---|---|---|
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Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
None
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001138136.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Apr 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cowden syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004019981.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
|
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Pathogenic
(Mar 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PTEN-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004103312.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The PTEN c.633C>A variant is predicted to result in premature protein termination (p.Cys211*). This variant has been reported in individuals with PTEN hamartoma tumor syndrome … (more)
The PTEN c.633C>A variant is predicted to result in premature protein termination (p.Cys211*). This variant has been reported in individuals with PTEN hamartoma tumor syndrome with both inherited and de novo cases reported (Table 1, Zhou et al 2001. PubMed ID: 11476841; Figure 1, Wanner et al. 2001. PubMed ID: 11174374; Table 1, Sarquis et al. 2006. PubMed ID: 16773562). This variant is reported in 1 of ~249,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/10-89712015-C-A) and is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/7836/). Nonsense variants in PTEN are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 21, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450276.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
|
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Pathogenic
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Cowden syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000487763.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Jun 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001773412.2
First in ClinVar: Aug 07, 2021 Last updated: Jun 24, 2023 |
Comment:
Observed in individuals with a personal or family history consistent with pathogenic variants in PTEN (Wanner et al., 2001; Zhou et al., 2001; Kim et … (more)
Observed in individuals with a personal or family history consistent with pathogenic variants in PTEN (Wanner et al., 2001; Zhou et al., 2001; Kim et al., 2005; Sarquis et al., 2006; Ngeow et al., 2011; Pilarski et al., 2011; Ha et al., 2012; Ngeow et al., 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29785012, 16773562, 22371648, 21956414, 24778394, 21659347, 11476841, 11174374, 10978354, 16007494, 25525159, 9467011, 33726816, 30720243, 21194675) (less)
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Pathogenic
(Dec 22, 2022)
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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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000961084.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 7836). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 7836). This premature translational stop signal has been observed in individual(s) with Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS), collectively also known as PTEN hamartoma tumor syndrome (PMID: 11476841, 16007494, 16773562, 21659347, 21956414, 22371648, 24778394). This variant is present in population databases (rs121909232, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Cys211*) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). (less)
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Pathogenic
(Jul 27, 2022)
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criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000579964.6
First in ClinVar: Jun 25, 2017 Last updated: May 01, 2024 |
Comment:
The p.C211* pathogenic mutation (also known as c.633C>A), located in coding exon 6 of the PTEN gene, results from a C to A substitution at … (more)
The p.C211* pathogenic mutation (also known as c.633C>A), located in coding exon 6 of the PTEN gene, results from a C to A substitution at nucleotide position 633. This changes the amino acid from a cysteine to a stop codon within coding exon 6. This alteration has been reported in multiple individuals with a PTEN-related disorder (Zhou XP et al. Lancet. 2011;358(9277):210-1; Pilarski R et al. J Med Genet. 2011;48(8):505-12; Ngeow, J et al. J Clin Oncol. 2014 Jun 10;32(17):1818-24). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Sep 01, 2000)
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no assertion criteria provided
Method: literature only
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MALIGNANT MELANOMA, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000028491.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Celebi et al. (2000) examined 21 metastatic melanoma samples and identified a C-to-A transversion at nucleotide 633 in exon 6 of the PTEN gene, resulting … (more)
Celebi et al. (2000) examined 21 metastatic melanoma samples and identified a C-to-A transversion at nucleotide 633 in exon 6 of the PTEN gene, resulting in a cys211-to-ter mutation. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808929.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
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: SCV001959417.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Comment:
Comment:
The PTEN c.633C>A variant is predicted to result in premature protein termination (p.Cys211*). This variant has been reported in individuals with PTEN hamartoma tumor syndrome with both inherited and de novo cases reported (Table 1, Zhou et al 2001. PubMed ID: 11476841; Figure 1, Wanner et al. 2001. PubMed ID: 11174374; Table 1, Sarquis et al. 2006. PubMed ID: 16773562). This variant is reported in 1 of ~249,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/10-89712015-C-A) and is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/7836/). Nonsense variants in PTEN are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
Observed in individuals with a personal or family history consistent with pathogenic variants in PTEN (Wanner et al., 2001; Zhou et al., 2001; Kim et al., 2005; Sarquis et al., 2006; Ngeow et al., 2011; Pilarski et al., 2011; Ha et al., 2012; Ngeow et al., 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29785012, 16773562, 22371648, 21956414, 24778394, 21659347, 11476841, 11174374, 10978354, 16007494, 25525159, 9467011, 33726816, 30720243, 21194675)
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 7836). This premature translational stop signal has been observed in individual(s) with Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS), collectively also known as PTEN hamartoma tumor syndrome (PMID: 11476841, 16007494, 16773562, 21659347, 21956414, 22371648, 24778394). This variant is present in population databases (rs121909232, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Cys211*) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675).
Comment:
The p.C211* pathogenic mutation (also known as c.633C>A), located in coding exon 6 of the PTEN gene, results from a C to A substitution at nucleotide position 633. This changes the amino acid from a cysteine to a stop codon within coding exon 6. This alteration has been reported in multiple individuals with a PTEN-related disorder (Zhou XP et al. Lancet. 2011;358(9277):210-1; Pilarski R et al. J Med Genet. 2011;48(8):505-12; Ngeow, J et al. J Clin Oncol. 2014 Jun 10;32(17):1818-24). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
The PTEN c.633C>A variant is predicted to result in premature protein termination (p.Cys211*). This variant has been reported in individuals with PTEN hamartoma tumor syndrome with both inherited and de novo cases reported (Table 1, Zhou et al 2001. PubMed ID: 11476841; Figure 1, Wanner et al. 2001. PubMed ID: 11174374; Table 1, Sarquis et al. 2006. PubMed ID: 16773562). This variant is reported in 1 of ~249,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/10-89712015-C-A) and is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/7836/). Nonsense variants in PTEN are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
Observed in individuals with a personal or family history consistent with pathogenic variants in PTEN (Wanner et al., 2001; Zhou et al., 2001; Kim et al., 2005; Sarquis et al., 2006; Ngeow et al., 2011; Pilarski et al., 2011; Ha et al., 2012; Ngeow et al., 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29785012, 16773562, 22371648, 21956414, 24778394, 21659347, 11476841, 11174374, 10978354, 16007494, 25525159, 9467011, 33726816, 30720243, 21194675)
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 7836). This premature translational stop signal has been observed in individual(s) with Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS), collectively also known as PTEN hamartoma tumor syndrome (PMID: 11476841, 16007494, 16773562, 21659347, 21956414, 22371648, 24778394). This variant is present in population databases (rs121909232, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Cys211*) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675).
Comment:
The p.C211* pathogenic mutation (also known as c.633C>A), located in coding exon 6 of the PTEN gene, results from a C to A substitution at nucleotide position 633. This changes the amino acid from a cysteine to a stop codon within coding exon 6. This alteration has been reported in multiple individuals with a PTEN-related disorder (Zhou XP et al. Lancet. 2011;358(9277):210-1; Pilarski R et al. J Med Genet. 2011;48(8):505-12; Ngeow, J et al. J Clin Oncol. 2014 Jun 10;32(17):1818-24). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| A case of Cowden syndrome diagnosed from multiple gastric polyposis. | Ha M | World journal of gastroenterology | 2012 | PMID: 22371648 |
| 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 |
| Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features. | Pilarski R | Journal of medical genetics | 2011 | PMID: 21659347 |
| A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. | Tan MH | American journal of human genetics | 2011 | PMID: 21194675 |
| Distinct expression profiles for PTEN transcript and its splice variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. | Sarquis MS | American journal of human genetics | 2006 | PMID: 16773562 |
| Analysis of PTEN gene mutations in Korean patients with Cowden syndrome and polyposis syndrome. | Kim DK | Diseases of the colon and rectum | 2005 | PMID: 16007494 |
| Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes. | Zhou X | Lancet (London, England) | 2001 | PMID: 11476841 |
| Identification of PTEN mutations in metastatic melanoma specimens. | Celebi JT | Journal of medical genetics | 2000 | PMID: 10978354 |
| 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 |
| Appendectomy, tonsillectomy, and neoplasia. | Lee Y | Journal of surgical oncology | 1975 | PMID: 1097835 |
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Text-mined citations for rs121909232 ...
HelpThese 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 03, 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.