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

Total submissions: 25

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	2021-05-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: decreased protein expression and stability, increased pAKT and pERK signaling (He et al., 2013); Nonsense variant in the C-terminus predicted to result in protein truncation as the last 69 amino acids are lost, disrupting the critical C2 domain (Wang et al., 2008); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25344691, 14518070, 16410744, 21798893, 22675565, 24778394, 23619167, 23695273, 22381246, 29608813, 28475857, 33600059, 10749983, 25756585, 11875759, 10353779, 11685670, 10848731, 21956414, 17392703, 15633233, 16618716, 17515920, 18772396, 23917401, 11555573, 10092130, 27165089, 27563534, 27797976, 17526801, 25549896, 23470840, 9399897, 23475934, 25288137, 27959697, 28724667, 29909963, 28526761, 22595938, 28152038, 31086789, 30233642, 31023376, 30426508, 30528446, 18626510, 23335809, 32238909, 31447099, 32581362, 33509259)
Invitae	RCV000197423	SCV000253834	pathogenic	PTEN hamartoma tumor syndrome	2020-10-05	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 Health, Inc	RCV000162409	SCV000691135	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-12	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 8 of the PTEN gene, creating a premature translation stop signal in the penultimate exon. A functional study has shown that the variant causes decrease in PTEN RNA transcript and protein expression (PMID: 23475934). This variant has been reported in individuals affected with PTEN hamartoma tumor syndrome (PMID: 9467011, 10232405, 10353779, 10400993, 10848731, 11685670, 11918710, 11685670, 18558293, 22595938, 23475934, 23695273, 23934601, 24052722, 24778394, 25549896, 28526761) and has been shown to segregate with disease in at least two of the families (PMID: 10353779, 11685670). This variant has also been reported to arise de novo in some of these individuals (PMID: 22595938, 24052722, 25549896, 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.
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000078601	SCV001744459	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000078601	SCV001807915	pathogenic	not provided		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000078601	SCV001958254	pathogenic	not provided		no assertion criteria provided	clinical testing