ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.697C>T (p.Arg233Ter) (rs121909219)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162649 SCV000213087 pathogenic Hereditary cancer-predisposing syndrome 2017-10-17 criteria provided, single submitter clinical testing The p.R233* pathogenic mutation (also known as c.697C>T) located in coding exon 7 of the PTEN gene, results from a C to T substitution at nucleotide position 697. This changes the amino acid from an arginine to a stop codon within coding exon 7. This mutation was first reported in a patient with Cowden disease (Liaw D et al. Nat Genet. 1997;16(1):64-67). Subsequently, this mutation has been identified in numerous families with features in the PTEN Hamartoma Tumor Syndrome (PHTS) spectrum, including macrocephaly, intellectual disability, trichilemmomas, gastrointestinal polyps, thyroid lesions, mucosal neuromas, cutaneous lipomas, breast cancer, and endometrial cancer (Marsh DJ et al. Hum. Mol. Genet. 1999 Aug;8(8):1461-72, Sawada T et al. Jpn. J. Cancer Res. 2000 Jul;91(7):700-5, Sawada T et al. Am. J. Med. Genet. A 2004 Jul;128A(1):12-4, Buisson P et al. J. Pediatr. Surg. 2006 Sep;41(9):1601-3, Lachlan KL et al. J. Med. Genet. 2007 Sep;44(9):579-85; Saletti V et al. Eur J Med Genet, 2017 May;60:261-264). Furthermore, in vitro studies showed a significant reduction in PTEN protein expression while mRNA levels remained comparable to wild-type suggesting post translational protein degradation. Additional in vitro studies showed increased proteasome activity in cells with this mutation compared to wild-type. Authors suggested a possible association with the increased proteasome activity and an increased risk for neurologic manifestations (He et al. Cancer Res. 2013. 73(10):3029-3040). 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.
GeneDx RCV000212882 SCV000222225 pathogenic not provided 2018-06-07 criteria provided, single submitter clinical testing This variant is denoted PTEN c.697C>T at the cDNA level and p.Arg233Ter (R233X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported multiple individuals with features of PTEN hamartoma tumor syndrome, and has been reported to occur de novo as well as to segregate with disease in multiple kindreds (Liaw 1997, Marsh 1998, Busch 2013, Gosein 2016, Tsujita 2016, Saletti 2017). We consider this variant to be pathogenic.
Invitae RCV000128455 SCV000260924 pathogenic PTEN hamartoma tumor syndrome 2019-12-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg233*) in the PTEN gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with Cowden syndrome (CS), CS-like phenotypes, Bannayan-Zonana syndrome, and PTEN hamartoma tumor syndrome (PHTS) (PMID: 24778394, 23470840, 9140396, 21956414, 10920277, 18558293, 9241266). ClinVar contains an entry for this variant (Variation ID: 7813). Experimental studies have shown that the p.Arg233* truncated protein is degraded and absent in cells derived from an individual with PHTS (PMID: 23475934). Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). For these reasons, this variant has been classified as Pathogenic.
Color RCV000162649 SCV000537671 pathogenic Hereditary cancer-predisposing syndrome 2020-03-09 criteria provided, single submitter clinical testing
Herman Laboratory,Nationwide Children's Hospital RCV000128455 SCV000579286 pathogenic PTEN hamartoma tumor syndrome 2017-03-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999749 SCV000604975 pathogenic none provided 2019-09-30 criteria provided, single submitter clinical testing The PTEN c.697C>T; p.Arg233Ter variant (rs121909219) has been described in the literature in multiple individuals affected with Cowden syndrome (He 2013, Liaw 1997, Ngeow 2014, Sawada 2000). In at least one case, this variant was found in an affected individual but was not present in either parent, suggesting a de novo origin (Sawada 2000). Functional studies show that this variant leads to increased proteasomal degradation of PTEN protein (He 2013). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 7813), and it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: He X et al. Cowden syndrome-related mutations in PTEN associate with enhanced proteasome activity. Cancer Res. 2013 May 15;73(10):3029-40. Liaw D et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997 May;16(1):64-7. Ngeow J et al. Second malignant neoplasms in patients with Cowden syndrome with underlying germline PTEN mutations. J Clin Oncol. 2014 Jun 10;32(17):1818-24. Sawada T et al. Mutation analysis of the PTEN / MMAC1 gene in Japanese patients with Cowden disease. Jpn J Cancer Res. 2000 Jul;91(7):700-5.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000008256 SCV000840054 pathogenic Cowden syndrome 1 2018-03-29 criteria provided, single submitter clinical testing This c.697C>T (p.Arg233*) variant in exon 7 of the PTEN gene creates a stop gain which is predicted to lead to nonsense-mediated mRNA decay, which is a known disease mechanism for this gene. This variant has been reported in multiple individuals and families with Cowden Syndrome, Bannayan-Riley-Ruvalcaba syndrome and other forms of cancer (PMID: 9140396, 9241266, 10400993, 17526800, 23470840, 24778394). It has also been found to be de novo in some patients with Cowden Syndrome and Bannayan-Riley-Ruvalcaba syndrome (PMID: 10920277, 16952599) and is extremely rare in the general population. Therefore, the c.697C>T (p.Arg233*) variant in the PTEN gene is classified as pathogenic.
Academic Department of Medical Genetics, University of Cambridge RCV000162649 SCV000992196 pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Integrated Genetics/Laboratory Corporation of America RCV000678740 SCV001362393 pathogenic Cowden syndrome 2019-07-18 criteria provided, single submitter clinical testing Variant summary: PTEN c.697C>T (p.Arg233X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251444 control chromosomes (gnomAD). c.697C>T has been reported in the literature in several individuals affected with Cowden Syndrome (CS) or CS-like phenotypes (including Tan_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated the lack of the truncated protein product in transfected cell lines (He_2013). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000128455 SCV001423839 pathogenic PTEN hamartoma tumor syndrome criteria provided, single submitter research The PTEN c.697C>T [p.R233*] variant is a well described pathogenic variant observed in multiple hamartoma syndrome and/or macrocephaly (PMID:9140396; 9241266; 9399897; 10920277; 17526800; 18558293). This variant is predicted to cause premature termination of the PTEN protein, which may lead to aberrant or absent PTEN.
OMIM RCV000008256 SCV000028463 pathogenic Cowden syndrome 1 1997-08-01 no assertion criteria provided literature only
Medical Molecular Genetics,University of Birmingham RCV000128455 SCV000172156 pathogenic PTEN hamartoma tumor syndrome 2012-07-01 no assertion criteria provided clinical testing Clinically treated as causative
Pathway Genomics RCV000008256 SCV000189987 pathogenic Cowden syndrome 1 2014-07-24 no assertion criteria provided clinical testing
Database of Curated Mutations (DoCM) RCV000434092 SCV000504399 pathogenic Neoplasm of the large intestine 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444248 SCV000504400 pathogenic Non-small cell lung cancer 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427583 SCV000504401 pathogenic Breast neoplasm 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436969 SCV000504402 not provided Glioblastoma 2016-03-10 no assertion provided literature only
OMIM RCV000477737 SCV000564211 pathogenic Macrocephaly/autism syndrome 1997-08-01 no assertion criteria provided literature only
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678740 SCV000804912 pathogenic Cowden syndrome 2014-03-21 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785383 SCV000923954 pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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