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. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. 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 previously described in cohorts of patients with Cowden disease or Bannayan-Riley-Ruvalcaba syndrome (BRRS) (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), 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.
ClinVar Genomic variation as it relates to human health
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- Interpretation:
-
Pathogenic
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 2
- First in ClinVar:
- Dec 19, 2017
- Most recent Submission:
- Feb 7, 2023
- Last evaluated:
- Oct 19, 2021
- Accession:
- VCV000229705.11
- Variation ID:
- 229705
- Description:
- single nucleotide variant
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NM_000314.8(PTEN):c.209+1G>T
- Allele ID
- 233847
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 10q23.31
- Genomic location
- 10: 87925558 (GRCh38) GRCh38 UCSC
- 10: 89685315 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000314.8:c.209+1G>T MANE Select splice donor NM_001304717.5:c.729+1G>T splice donor NM_001304718.2:c.-541-5488G>T 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
- -
- Canonical SPDI
- NC_000010.11:87925557:G:T
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- -
- Links
- ClinGen: CA10578911
- dbSNP: rs1554897280
- VarSome
Help
Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Pathogenic | 1 | criteria provided, single submitter | Oct 19, 2021 | RCV000213295.3 | |
| Pathogenic | 1 | criteria provided, single submitter | Aug 31, 2021 | RCV000810652.7 |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Pathogenic
(Oct 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000273014.6
First in ClinVar: May 29, 2016 Last updated: Nov 29, 2022 |
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. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. 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 previously described in cohorts of patients with Cowden disease or Bannayan-Riley-Ruvalcaba syndrome (BRRS) (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), 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)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Aug 31, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
PTEN hamartoma tumor syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000950877.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023 |
Comment:
This sequence change affects a donor splice site in intron 3 of the PTEN gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 3 of the PTEN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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 is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individuals with Cowden syndrome (PMID: 20600018, 21194675, 21659347, 24778394). ClinVar contains an entry for this variant (Variation ID: 229705). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
Functional evidence
Help| 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 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 |
| 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...
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 Feb 07, 2023