ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.1003C>T (p.Arg335Ter) (rs121909231)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078601 SCV000110457 pathogenic not provided 2012-08-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622262 SCV000212745 pathogenic Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing
GeneDx RCV000078601 SCV000222135 pathogenic not provided 2018-11-30 criteria provided, single submitter clinical testing This pathogenic variant is denoted PTEN c.1003C>T at the cDNA level and p.Arg335Ter (R335X) 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 protein truncation. PTEN Arg335Ter, previously published as PTEN R334X using alternate numbering, is a recurrent pathogenic variant that has been reported de novo and to segregate with disease in multiple kindreds with features of PTEN Hamartoma Tumor syndrome (Lynch 1997, Kubo 2000, Zhou 2000, Bubien 2013, Busch 2013, Busa 2014, Wong 2018). On functional interrogation, PTEN Arg335Ter was associated with diminished mRNA and protein levels (He 2013). Based on current evidence, we consider this variant to be pathogenic.
Invitae RCV000197423 SCV000253834 pathogenic PTEN hamartoma tumor syndrome 2019-12-12 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the PTEN gene (p.Arg335*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 69 amino acids of the PTEN protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with PTEN hamartoma tumor syndrome (PHTS) (PMID: 24052722, 9467011, 10400993, 9399897), and was reported to segregate with PHTS in several families (PMID: 10353779, 9399897, 11685670). This variant has also been shown to have arisen de novo in some affected individuals (PMID: 10749983, 10232405). ClinVar contains an entry for this variant (Variation ID: 7833). Experimental studies have shown that this nonsense change generates an unstable mRNA and protein product (PMID: 9399897, 23475934). For these reasons, this variant has been classified as Pathogenic.
Herman Laboratory,Nationwide Children's Hospital RCV000197423 SCV000579258 pathogenic PTEN hamartoma tumor syndrome 2017-03-01 criteria provided, single submitter clinical testing
Counsyl RCV000033179 SCV000677738 pathogenic Cowden syndrome 1 2017-03-09 criteria provided, single submitter clinical testing
Color RCV000162409 SCV000691135 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000197423 SCV000711447 pathogenic PTEN hamartoma tumor syndrome 2016-06-22 criteria provided, single submitter clinical testing The p.Arg335X variant in PTEN has been reported in >9 individuals with Cowden or Bannayan-Zonana syndrome and segregated with disease with in five affected rela tives from 3 families (Lynch 1997, Ngeow 2011, He 2013, Ngeow 2014). It was also absent from large population studies. In vitro functional studies provide some evidence that the Arg335X variant impacts protein function (He 2013, Lumb 2013). This nonsense variant leads to a premature termination codon at position 335. T his alteration occurs within the terminal 50 bases of the second to last exon an d may escape nonsense mediated decay (NMD) resulting in a truncated protein. In summary, this variant meets our criteria to be classified as pathogenic for PTEN hamartoma tumor syndrome in an autosomal dominant manner.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000033179 SCV000782246 pathogenic Cowden syndrome 1 2016-11-01 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV000677405 SCV000803708 pathogenic PTEN-related disorder 2018-03-05 criteria provided, single submitter clinical testing
Baylor Genetics RCV000679881 SCV000807269 pathogenic Macrocephaly/autism syndrome; Cowden syndrome 1 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found twice in our laboratory: de novo in a 2-year-old female with global delays, hypotonia, macrocephaly, epilepsy, swallowing difficulty, abnormal muscle fibers; maternally inherited in a 6-year-old female with hypotonia, sleep apnea, GERD, chronic lung disease, laryngomaliacia, macrocephaly, polydactyly, atrial septal defect, decreased hearing, possible dysautonomia
Fulgent Genetics,Fulgent Genetics RCV000763223 SCV000893850 pathogenic Macrocephaly/autism syndrome; Meningioma, familial; Malignant tumor of prostate; VACTERL association with hydrocephalus; Glioma susceptibility 2; PTEN hamartoma tumor syndrome; Cowden syndrome 1 2018-10-31 criteria provided, single submitter clinical testing
Academic Department of Medical Genetics, University of Cambridge RCV000162409 SCV000992197 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.
Cavalleri Lab, Royal College of Surgeons in Ireland RCV000414819 SCV001160807 pathogenic Macrocephaly/autism syndrome 2019-12-11 criteria provided, single submitter research ACMG evidence PVS1, PS2, PM2
Ambry Genetics RCV000162409 SCV001169754 pathogenic Hereditary cancer-predisposing syndrome 2018-10-09 criteria provided, single submitter clinical testing The p.R335* pathogenic mutation (also known as c.1003C>T), located in coding exon 8 of the PTEN gene, results from a C to T substitution at nucleotide position 1003. This changes the amino acid from an arginine to a stop codon within coding exon 8. This mutation has been reported in several individuals and/or families with clinical manifestations of the PTEN hamartoma tumor syndrome (PHTS) including Cowden or Cowden-like syndrome (Ngeow J et al. J. Clin. Endocrinol. Metab. 2011 Dec;96:E2063-71; Lynch ED et al. Am. J. Hum. Genet. 1997 Dec;61:1254-60; Mester JL et al. Urology. 2012 May;79:1187.e1-7; Busch RM et al. Genet. Med. 2013 Jul;15:548-53; Kubo Y et al. Br. J. Dermatol. 2000 Jun;142:1100-5;Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Whitworth J et al. Am. J. Hum. Genet. 2018 Jul;103(1):3-18), Proteus-like syndrome (Zhou XP et al. Hum. Mol. Genet. 2000 Mar;9:765-8), and Bannayan-Riley-Ruvalcaba syndrome (Tok Celebi J et al. Exp. Dermatol. 1999 Apr;8:134-9; Hobert JA et al. Eur. J. Hum. Genet. 2014 Feb;22:273-6; Posey JE et al. N. Engl. J. Med. 2017 01;376(1):21-31). In an in vitro study this mutation was shown to significantly reduce protein expression and significantly elevate proteasome activity. The authors suggested that patients with mutations causing elevated proteasome activity could have more neurological manifestations than those with mutations that do not lead to elevated activity (He X et al. Cancer Res. 2013 May;73:3029-40). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Integrated Genetics/Laboratory Corporation of America RCV001174674 SCV001337906 pathogenic Cowden syndrome 2020-01-10 criteria provided, single submitter clinical testing Variant summary: PTEN c.1003C>T (p.Arg335X) 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 250932 control chromosomes. c.1003C>T has been frequently reported in the literature in multiple individuals affected with Cowden Syndrome, breast cancer and overlapping features of PTEN Hamartoma Tumor Syndromes (example, Lynch_1997, Nizialek_2015, Momozawa_2018, Celebi_1999). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of mutant transcripts consistent with degradation of these transcripts through a nonsense-mediated pathway and loss of heterozygosity in tumors (Lynch_1997). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000033179 SCV000028486 pathogenic Cowden syndrome 1 2007-07-01 no assertion criteria provided literature only
OMIM RCV000008281 SCV000028488 pathogenic Proteus-like syndrome 2007-07-01 no assertion criteria provided literature only
Baylor Genetics RCV000414819 SCV000328718 pathogenic Macrocephaly/autism syndrome 2015-01-29 no assertion criteria provided clinical testing Our laboratory reported dual molecular diagnoses in DNM1 (NM_001005336.1, c.465_467dup) and PTEN (NM_000314.4, c.1003C>T) in one individual with reported features of global developmental delay with concern for regression, speech delay, hypotonia, macrocephaly, seizure disorder, swallowing difficulty. The PTEN variant has been previously reported as disease causing [PMID 9399897, 21956414, 10749983]. Additionally, this variant was found once in our laboratory maternally inherited in a 6-year-old female with hypotonia, chronic lung disease, macrocephaly, polydatyly, atrial septal defect, dysautonomia.
Database of Curated Mutations (DoCM) RCV000437329 SCV000505651 likely pathogenic Neoplasm of brain 2015-07-14 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785564 SCV000924136 pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence, RCV000033179 SCV001245474 uncertain significance Cowden syndrome 1 no assertion criteria provided clinical testing

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