ClinVar Genomic variation as it relates to human health

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.

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.

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.

This nonsense variant causes the premature termination of PTEN protein synthesis. In addition, it has been reported in individuals affected with Cowden syndrome, Bannayan-Zonana syndrome, and PTEN hamartoma tumor syndrome in the published literature (PMID: 31336731 (2019), 24778394 (2014), 10920277 (2000), 9241266 (1997), 9140396 (1997)). Experimental studies indicate the truncated protein is unstable and associated with proteasome hyperactivity (PMID: 23475934 (2013)). Based on the available information, this variant is classified as pathogenic.

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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251444 control chromosomes. c.697C>T has been reported in the literature in multiple individuals affected with Cowden Syndrome and Hamartoma tumour syndrome (Tan_2011, Ciaccio_2019, Pena-Couso_2022), including at least one case in which the variant was reported as being aquired de novo. 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 protein including the truncated protein product in transfected cell lines (He_2013). Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

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. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Cowden syndrome (CS), CS-like phenotypes, Bannayan-Zonana syndrome, and PTEN hamartoma tumor syndrome (PHTS) (PMID: 9140396, 9241266, 10920277, 18558293, 21956414, 23470840, 24778394). ClinVar contains an entry for this variant (Variation ID: 7813). For these reasons, this variant has been classified as Pathogenic.

This variant changes 1 nucleotide in exon 7 of the PTEN gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Cowden syndrome, Bannayan-Zonana syndrome, and PTEN hamartoma tumor syndrome (PMID: 9140396, 9241266, 10920277, 18558293, 21956414, 23470840, 24778394, 27426521, 28286253, 28526761). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PTEN function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

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.

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; Reported in 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 referred for genetic testing at GeneDx and in published literature (Liaw et al., 1997; Marsh et al., 1998; Busch et al., 2013; Gosein et al., 2016; Tsujita et al., 2016; Saletti et al., 2017); Published functional studies demonstrate a damaging effect: decreased PTEN protein expression, increased phosphorylated AKT and ERK in patient cells (He et al., 2013); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27488391, 23475934, 24778394, 9467011, 21956414, 9140396, 27426521, 25288137, 23399955, 23470840, 26350204, 27009459, 24705275, 28286253, 28152038, 28724667, 29430632, 29909963, 31336731, 31362757, 26678657, 27703620, 18558293, 30528446, 31447099, 32581362, 34268892, 32003824, 33509259, 33258288, 33294277, 29152901, 31594918, 30787465)

This variant changes 1 nucleotide in exon 7 of the PTEN gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Cowden syndrome, Bannayan-Zonana syndrome, and PTEN hamartoma tumor syndrome (PMID: 9140396, 9241266, 10920277, 18558293, 21956414, 23470840, 24778394, 27426521, 28286253, 28526761). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PTEN function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

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 has been identified in numerous families with features on 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 (Liaw D et al. Nat Genet. 1997;16(1):64-67; 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; Ciaccio C et al. Eur J Med Genet 2019 Dec;62(12):103596). 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.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with ­hamartoma tumour syndrome (MONDO#0017623). Loss of function is the mechanism for null variants while missense variants have been demonstrated to exert either a loss of function or dominant-negative mechanism (GeneReviews). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In particular, PTEN-related Proteus syndrome has been described to be a highly variable disorder (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in individuals with PTEN hamatoma tumour syndrome, Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

PTEN: PVS1, PM2

The PTEN c.697C>T variant is predicted to result in premature protein termination (p.Arg233*). This variant has been reported in individuals with PTEN hamartoma tumor syndrome, in some cases with de novo occurrence (Liaw et al .1997. PubMed ID: 9140396; Ngeow et al. 2014. PubMed ID: 24778394; Kaymakcalan et al. 2021. PubMed ID: 34268892; Pena-Couso et al. 2022. PubMed ID: 35227301; Wang et al. 2022. PubMed ID: 36453251). It has also been reported in an individual with epilepsy and an individual with mild autism spectrum disorder and macrocephaly (Ronzano et al. 2022. PubMed ID: 35780606; Kaymakcalan et al. 2021. PubMed ID: 34268892). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in PTEN are expected to be pathogenic. This variant is interpreted as pathogenic.

Clinically treated as causative

Recurrent pathogenic variants