Submissions for variant NM_000314.8(PTEN):c.388C>T (p.Arg130Ter)

gnomAD frequency: 0.00001  dbSNP: rs121909224

Total submissions: 42

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132187	SCV000187267	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-08	criteria provided, single submitter	clinical testing	The p.R130* pathogenic mutation (also known as c.388C>T), located in coding exon 5 of the PTEN gene, results from a C to T substitution at nucleotide position 388. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been reported in numerous individuals diagnosed with Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, breast cancer, thyroid cancer, renal cancer, and/or other clinical features associated with PTEN mutations (Nelen MR et al. Hum. Molec. Genet. 1997 Aug;6:1383-7; Mester JL et al. Urology. 2012 May;79:1187.e1-7; Shuch B et al. J. Urol. 2013 Dec;190:1990-8; Ngeow J et al. J. Clin. Endocrinol. Metab. 2011 Dec;96:E2063-71; Heindl M et al. Gastroenterology. 2012 May;142:1093-6.e6; Busch RM et al Genet. Med. 2013 Jul;15:548-53; Nieuwenhuis MH et al. Fam. Cancer. 2014 Mar;13:57-63; Marsh DJ et al. Hum Mol Genet, 1998 Mar;7:507-15; Zori RT et al. Am J Med Genet, 1998 Dec;80:399-40; Kim RH et al. NPJ Genom Med, 2020 Sep;5:40; Yauy K et al. J Natl Compr Canc Netw, 2019 01;17:7-11; Kubo Y et al. Br J Dermatol, 2000 Jun;142:1100-5; Bouron-Dal Soglio D et al. Eur Thyroid J, 2018 Jan;7:44-50; Hansen-Kiss E et al. J Med Genet, 2017 07;54:471-478). 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	RCV000078615	SCV000222110	pathogenic	not provided	2021-10-18	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25525159, 10400993, 9259288, 24345843, 27168869, 24375884, 28315634, 10749983, 22266152, 23470840, 10848731, 21956414, 9467011, 9856571, 23335809, 22252256, 22595938, 17526801, 22446940, 17526800, 11918710, 19265751, 17286265, 27477328, 27157322, 26786923, 27553368, 26976419, 16773562, 29594054, 28152038, 28655553, 30287823, 30720243, 31166879, 30306255, 32369273, 33509259, 33083010)
Invitae	RCV000199099	SCV000253832	pathogenic	PTEN hamartoma tumor syndrome	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg130*) 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 present in population databases (rs121909224, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with PTEN hamartoma tumor syndrome (PMID: 9259288, 16773562, 21956414, 22266152, 23470840, 24345843, 28655553). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7819). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000008263	SCV000489500	pathogenic	Cowden syndrome 1	2016-10-13	criteria provided, single submitter	clinical testing
Herman Laboratory, Nationwide Children's Hospital	RCV000199099	SCV000579271	pathogenic	PTEN hamartoma tumor syndrome	2017-03-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000078615	SCV000604969	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing	The PTEN c.388C>T; p.Arg130Ter variant (rs121909224) has been reported in multiple individuals diagnosed with Cowden syndrome or PTEN hamartoma tumor syndrome (Busch 2013, Henderson 2014, Kubo 2000, Nelen 1997). The variant is reported in the ClinVar database (Variation ID: 7819) and in the general population with an allele frequency of 0.001% (3/251384 alleles) in the Genome Aggregation Database. 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: Busch R et al. Cognitive characteristics of PTEN hamartoma tumor syndromes. Genet Med. 2013; 15(7):548-53. Henderson C et al. Increased prevalence of eosinophilic gastrointestinal disorders in pediatric PTEN hamartoma tumor syndromes. J Pediatr Gastroenterol Nutr. 2014; 58(5):553-60. Kubo Y et al. A novel PTEN mutation in a Japanese patient with Cowden disease. Br J Dermatol. 2000; 142(6):1100-5. Nelen M et al. Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet. 1997; 6(8):1383-7.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000199099	SCV000967757	pathogenic	PTEN hamartoma tumor syndrome	2018-04-02	criteria provided, single submitter	clinical testing	The p.Arg130X variant in PTEN has been reported in at least 10 individuals with Cowden syndrome (a sub-type of PTEN hamartoma tumor syndrome) and segregated wit h disease in at least 5 affected relatives from 2 families (Nelen 1997, Marsh 19 98, Zori 1998, Kubo 2000, Ngeow 2011). This variant has been identified in 3/246 154 total chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad. broadinstitute.org; dbSNP rs121909224) and in ClinVar (Variation ID# 7819). This nonsense variant leads to a premature termination codon at position 130, which is predicted to lead to a truncated or absent protein. Heterozygous loss of func tion of the PTEN gene is an established disease mechanism in PTEN hamartoma tumo r syndrome. In summary, this variant meets criteria to be classified as pathogen ic for PTEN hamartoma tumor syndrome in an autosomal dominant manner. ACMG/AMP C riteria applied PVS1; PS4; PP1_Moderate.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000078615	SCV001134775	pathogenic	not provided	2019-08-26	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of PTEN protein synthesis. In addition, it has been reported in individuals with PTEN hamartoma tumor syndrome (PHTS) in the published literature (PMID: 9259288 (1997), 21956414 (2011), 23934601 (2014), 24345843 (2014), 28526761 (2017)). Based on the available information, this variant is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000078615	SCV001249159	pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132187	SCV001340966	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-21	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 5 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 (PMID: 9259288, 9467011, 9856571, 10400993, 10848731, 11332402, 11918710, 14566704, 16773562, 17286265, 20600018, 21194675, 21956414, 22266152, 23470840, 23764071, 30659124). It has been shown that this variant segregates with disease (PMID: 9259288, 9856571, 11332402) and has been observed de novo in an individual with Cowden syndrome (PMID: 11918710). This variant has been identified in 3/251384 chromosomes 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000008263	SCV001428573	pathogenic	Cowden syndrome 1	2017-10-12	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000078615	SCV001448140	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000132187	SCV001448935	pathogenic	Hereditary cancer-predisposing syndrome	2019-06-14	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV001542771	SCV001760260	pathogenic	Glioma susceptibility 2		criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000008263	SCV002059850	pathogenic	Cowden syndrome 1	2021-10-07	criteria provided, single submitter	clinical testing
DASA	RCV000008263	SCV002061182	pathogenic	Cowden syndrome 1	2022-01-05	criteria provided, single submitter	clinical testing	The c.388C>T;p.(Arg130*) variant creates a premature translational stop signal in the PTEN gene. It is expected to result in an absent or disrupted protein product -PVS1.This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 7819; OMIM: 601728.0007; PMID: 9259288; 21956414; 22266152; 23470840; 16773562; 24345843; 28655553) - PS4. The variant is present at low allele frequencies population databases (rs121909224 – gnomAD 0.001193%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant was assumed de novo, but without confirmation of paternity and maternity(PMID: 11918710) - PM6. The variant co-segregated with disease in multiple affected family members (PMID: 9259288; 9856571; 11332402) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000199099	SCV002525581	pathogenic	PTEN hamartoma tumor syndrome	2020-01-28	criteria provided, single submitter	clinical testing	The p.Arg130* variant replaces the arginine at position 130 with a premature termination codon and is expected to cause a loss of protein function. This variant has previously been reported in several patients with PTEN hamartoma tumor syndrome (PHTS), which includes Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS) (NBK1488, PMID: 10749983, 28655553, 9856571, and others). The phenotypic spectrum reported in PHTS includes vascular malformations (NBK1488, PMID: 28655553). This variant has been observed in large population studies at an allele frequency of 3/251,384 allele (Genome Aggregation Database).
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000008263	SCV002576484	pathogenic	Cowden syndrome 1		criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000008263	SCV002580289	pathogenic	Cowden syndrome 1	2021-08-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476944	SCV002793214	pathogenic	Macrocephaly-autism syndrome; Familial meningioma; Malignant tumor of prostate; Glioma susceptibility 2; Cowden syndrome 1	2022-03-15	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000008265	SCV003761297	pathogenic	Macrocephaly-autism syndrome	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Arg130Ter variant in PTEN was identified by our study in one individual with macrocephaly-autism syndrome (PMID: 32959437). Trio exome analysis showed this variant to be de novo. The p.Arg130Ter variant in PTEN has been previously reported in over 30 unrelated individuals with PTEN-associated disease (PMID: 29594054, PMID: 33083010, PMID: 24345843, PMID: 28655553, PMID: 28526761, PMID: 10400993, PMID: 14566704, PMID: 16773562, PMID: 11332402, PMID: 17286265, PMID: 20600018, PMID: 21194675, PMID: 23470840, PMID: 30659124, PMID: 23764071, PMID: 1191871, PMID: 10848731, PMID: 9467011, PMID: 9856571, PMID: 9259288, PMID: 21956414, SCV002059850.1) and segregated with disease in 17 affected relatives from 6 families (PMID: 28655553, PMID: 17286265, PMID: 30659124, PMID: 11332402, PMID: 9259288, PMID: 9856571), but has been identified in 0.003% (1/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121909224). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Pathogenic variants may be present at a low frequency in the general population, for diseases with clinical variability, or reduced penetrance. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 5 individuals with confirmed paternity and maternity (PMID: 28526761, PMID: 11918710, PMID: 32959437, PMID: 28526761, SCV002059850.1). This variant has also been reported in ClinVar (Variation ID: 7819) and has been interpreted as pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 130, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PTEN gene is an established disease mechanism in autosomal dominant PTEN-associated disease, including autosomal dominant macrocephaly-autism syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant macrocephaly-autism syndrome. ACMG/AMP Criteria applied: PVS1, PS2_VeryStrong, PS4, PP1_Strong (Richards 2015).
3billion	RCV000008263	SCV003841764	pathogenic	Cowden syndrome 1	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 11918710). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000007819 / PMID: 9259288). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Myriad Genetics, Inc.	RCV000008263	SCV004019961	pathogenic	Cowden syndrome 1	2023-04-05	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV003326115	SCV004032474	pathogenic	Macrocephaly-autism syndrome; Cowden syndrome 1	2023-08-11	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000008263	SCV004175664	pathogenic	Cowden syndrome 1	2023-06-22	criteria provided, single submitter	clinical testing	The PTEN c.388C>T missense variant has been classified as Pathogenic (PVS1, PM2, PS4_Moderate). The c.388C>T variant is located in exon 5/9 and introduces a premature stop codon resulting in a truncated protein (PMID: 11918710) and is predicted to undergo nonsense-mediated decay (PVS1). It is absent in gnomAD (PM2) and prevalent in affected individuals (PS4_moderate). The variant has been reported in PMID: 9259288 in 2 affected individuals within a family. PMID: 11918710 also reports this variant as de novo in an affected individual. This variant has been reported in dbSNP (rs121909224), ClinVar as pathogenic (ClinVar variant ID: 7819) and HGMD as disease causing (CM971273).
Baylor Genetics	RCV001542771	SCV004207132	pathogenic	Glioma susceptibility 2	2021-12-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532310	SCV004749777	pathogenic	PTEN-related disorder	2023-12-08	criteria provided, single submitter	clinical testing	The PTEN c.388C>T variant is predicted to result in premature protein termination (p.Arg130*). This variant has previously been reported to be causative for PTEN Hamartoma Tumor Syndrome (Heindl et al. 2012. PubMed ID: 22266152; Ngeow et al. 2011. PubMed ID: 21956414; Sarquis et al. 2006. PubMed ID: 16773562). This variant is reported in 3 of ~251,000 alleles in gnomAD and interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/7819/). Nonsense variants in PTEN are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000008263	SCV000028470	pathogenic	Cowden syndrome 1	2007-03-15	no assertion criteria provided	literature only
OMIM	RCV000008265	SCV000028472	pathogenic	Macrocephaly-autism syndrome	2007-03-15	no assertion criteria provided	literature only
Pathway Genomics	RCV000008263	SCV000189986	pathogenic	Cowden syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
Database of Curated Mutations (DoCM)	RCV000443514	SCV000504380	likely pathogenic	Neoplasm of brain	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424529	SCV000504381	pathogenic	Neoplasm of ovary	2014-10-02	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000078615	SCV000692010	pathogenic	not provided		no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000424529	SCV000923927	pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
University Health Network, Princess Margaret Cancer Centre	RCV000199099	SCV001430888	pathogenic	PTEN hamartoma tumor syndrome		no assertion criteria provided	clinical testing	The variant c.388C>T has rarely been reported in general population databases, however, it has been reported as pathogenic in ClinVar by multiple laboratories. It is a loss of function variant that was reported in ClinVar to be associated with Cowden Syndrome (RCV000008263.6) and PTEN hamartoma syndrome (RCV000199099.8).
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257555	SCV001434381	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation
MAGI's Lab - Research, MAGI Group	RCV001327978	SCV001437654	pathogenic	Abnormal cardiovascular system morphology		no assertion criteria provided	provider interpretation
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000078615	SCV001799589	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078615	SCV001956019	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000008263	SCV002034735	not provided	Cowden syndrome 1		no assertion provided	literature only	Recurrent pathogenic variants
Center for Molecular Medicine, Children’s Hospital of Fudan University	RCV000008265	SCV002073923	pathogenic	Macrocephaly-autism syndrome	2022-02-08	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162218	SCV002758067	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research