10-87933147-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000314.8(PTEN):c.388C>T(p.Arg130Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000274 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R130R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000314.8 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.388C>T | p.Arg130Ter | stop_gained | 5/9 | ENST00000371953.8 | |
PTEN | NM_001304717.5 | c.907C>T | p.Arg303Ter | stop_gained | 6/10 | ||
PTEN | NM_001304718.2 | c.-363C>T | 5_prime_UTR_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.388C>T | p.Arg130Ter | stop_gained | 5/9 | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251384Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135856
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461670Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727136
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cowden syndrome 1 Pathogenic:11Other:1
Pathogenic, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 12, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 13, 2016 | - - |
not provided, no classification provided | literature only | GeneReviews | - | Recurrent pathogenic variants - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 09, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jun 22, 2023 | 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 05, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Oct 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 15, 2007 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | 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. - |
not provided Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 01, 2019 | 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. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 26, 2019 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 18, 2021 | 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) - |
PTEN hamartoma tumor syndrome Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Herman Laboratory, Nationwide Children's Hospital | Mar 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 02, 2018 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | Jan 28, 2020 | 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). - |
Pathogenic, no assertion criteria provided | clinical testing | University Health Network, Princess Margaret Cancer Centre | - | 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). - |
Macrocephaly-autism syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 25, 2023 | 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). - |
Pathogenic, no assertion criteria provided | clinical testing | Center for Molecular Medicine, Children’s Hospital of Fudan University | Feb 08, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 15, 2007 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 21, 2021 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 08, 2021 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jun 14, 2019 | - - |
Glioma susceptibility 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 09, 2021 | - - |
Neoplasm of ovary Pathogenic:2
Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
PTEN-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 08, 2023 | 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. - |
Rhabdomyosarcoma Pathogenic:1
Pathogenic, no assertion criteria provided | provider interpretation | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Sep 01, 2020 | - - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Malignant tumor of prostate;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 15, 2022 | - - |
Macrocephaly-autism syndrome;CN072330:Cowden syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Aug 11, 2023 | - - |
Abnormal cardiovascular system morphology Pathogenic:1
Pathogenic, no assertion criteria provided | provider interpretation | MAGI's Lab - Research, MAGI Group | - | - - |
Neoplasm of brain Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at