ClinVar Genomic variation as it relates to human health
NM_000314.8(PTEN):c.209+1G>T
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.209+1G>T
Variation ID: 229705 Accession: VCV000229705.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q23.31 10: 87925558 (GRCh38) [ NCBI UCSC ] 10: 89685315 (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 19, 2017 Feb 14, 2024 Oct 19, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000314.8:c.209+1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001304717.5:c.729+1G>T splice donor NM_001304718.2:c.-541-5488G>T intron variant NC_000010.11:g.87925558G>T NC_000010.10:g.89685315G>T NG_007466.2:g.67120G>T LRG_311:g.67120G>T LRG_311t1:c.209+1G>T - Protein change
- Other names
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- Canonical SPDI
- NC_000010.11:87925557:G:T
- 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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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 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. |
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PTEN | Sufficient evidence for dosage pathogenicity | No evidence available | GRCh38 GRCh38 GRCh37 |
3002 | 3493 |
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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Pathogenic (1) |
criteria provided, single submitter
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Oct 19, 2021 | RCV000213295.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 13, 2019 | RCV000810652.8 |
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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Pathogenic
(Oct 19, 2021)
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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: SCV000273014.7 First in ClinVar: May 29, 2016 Last updated: Oct 28, 2023 |
Comment:
The c.209+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 3 of the PTEN gene. Alterations that disrupt … (more)
The c.209+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 3 of the PTEN gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant has been identified in patients with clinical features of PTEN hamartoma syndrome (Tan MH, et al. Am. J. Hum. Genet. 2011 Jan; 88(1):42-56; Pilarski R et al. J Med Genet, 2011 Aug;48:505-12; Ambry internal data), breast cancer (Ngeow J, et al. J. Clin. Oncol. 2014 Jun; 32(17):1818-24) and colon polyps, including ganglioneuromas (Heald B et al. Gastroenterology, 2010 Dec;139:1927-33). Another alteration impacting the same donor site (c.209+1G>A) has been detected in cohorts of patients with features of Cowden syndrome and/or BRRS (Marsh DJ et al. Hum. Mol. Genet., 1999 Aug;8:1461-72; Pilarski R et al. J Med Genet, 2011 Aug;48:505-12; Tan MH et al. Am J Hum Genet. 2011 Jan;88(1):42-56), and functional analysis using patient mRNA has shown that this transcript has significantly reduced protein phosphatase activity despite being in-frame and stable due to exon 3 skipping (Agrawal S et al. Hum Mol Genet, 2005 Aug;14:2459-68). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Nov 13, 2019)
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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: SCV000950877.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: … (more)
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant has been observed in several individuals affected with Cowden syndrome (PMID: 21194675, 24778394, 21659347, 20600018). ClinVar contains an entry for this variant (Variation ID: 229705). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 3 of the PTEN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. (less)
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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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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 |
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 |
Frequent gastrointestinal polyps and colorectal adenocarcinomas in a prospective series of PTEN mutation carriers. | Heald B | Gastroenterology | 2010 | PMID: 20600018 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
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 |
Text-mined citations for rs1554897280 ...
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.