NM_000314.8:c.388C>T

Variant names:

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.Arg130*) 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PTEN
NM_000314.8 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:44O:2

Conservation

PhyloP100: 5.57

Variant links:

Genes affected

PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

PTEN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-87933147-C-T is Pathogenic according to our data. Variant chr10-87933147-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87933147-C-T is described in Lovd as [Likely_pathogenic]. Variant chr10-87933147-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8 link	c.388C>T	p.Arg130*	stop_gained	Exon 5 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304718.2 link	c.-363C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 4 of 9		NP_001291647.1	P60484
PTEN	NM_001304717.5 link	c.907C>T	p.Arg303*	stop_gained	Exon 6 of 10		NP_001291646.4	P60484
PTEN	NM_001304718.2 link	c.-363C>T		5_prime_UTR_variant	Exon 4 of 9		NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 link	c.388C>T	p.Arg130*	stop_gained	Exon 5 of 9	1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251384

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461670

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:44Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cowden syndrome 1

Pathogenic:12Other:1

Jul 24, 2014

Pathway Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Cowden syndrome 1 (MIM#158350). 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 (PMID: 20301661). (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 (PMID: 20301661). (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) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants have been reported as pathogenic (ClinVar). (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 hamartoma 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 -

Oct 13, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Recurrent pathogenic variants -

Oct 12, 2017

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2021

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 09, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2023

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Apr 05, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not provided

Pathogenic:10

Nov 01, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Aug 26, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Oct 18, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 06, 2021

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 30, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A PTEN c.388C>T p.Arg130* variant was identified at a near heterozygous allelic fraction of 48.5%, a frequency which may be consistent with germline origin. This variant has been identified in a germline state in numerous individuals with PTEN Hamartoma Tumor syndrome (PHTS) (Yauy K et al., PMID: 30659124; Yehia L et al., PMID: 29684080; Herman GE et al., PMID: 17286265; Bussaglia E et al., PMID: 11918710; Bonneau D et al., PMID: 10923032). It has also been identified in a somatic state in several individuals with PHTS, who also harbored a second variant (Tan WH et al., PMID: 17526801; Paolacci S et al., PMID: 33105631; Zhou XP et al., PMID: 10749983). There are 165 cases with this variant in the cancer database COSMIC (COSMIC ID: COSV64288463). This variant has been reported in the ClinVar database as a pathogenic variant by multiple submitters in both a germline and somatic state (ClinVar ID: 7819). It is only observed on 4/1,613,740 alleles in the general population (gnomAD v.4.1.0), indicating it is not a common variant. This single nucletide variant results in a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on the ACMG/AMP guidelines (Richards S et al., PMID:25741868) and gene-specific practices from the ClinGen Criteria Specification Registry (Mester JL et al., PMID: 30311380), this variant is classified as pathogenic. -

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PTEN hamartoma tumor syndrome

Pathogenic:5

Mar 01, 2017

Herman Laboratory, Nationwide Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jan 28, 2020

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Apr 02, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

University Health Network, Princess Margaret Cancer Centre

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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). -

Macrocephaly-autism syndrome

Pathogenic:3

Feb 08, 2022

Center for Molecular Medicine, Children’s Hospital of Fudan University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 25, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Mar 15, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Jul 25, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jun 14, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

PTEN-related disorder

Pathogenic:2

Jun 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

May 12, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant found in exon 5 of 9 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in PTEN is an established mechanism of disease (PMID: 30738865). This variant has been previously reported as a heterozygous change in individuals with Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome and macrocephaly/autism syndrome (PMID: 9259288, 9856571, 17286265, 19265751, 33372952, 33083010, 24345843, 23470840). The c.388C>T (p.Arg130Ter) variant is present in the heterozygous state in the gnomAD v4 population database at a frequency of 0.0003% (4/1461670) and thus is presumed to be rare. Based on the available evidence, c.388C>T (p.Arg130Ter) is classified as Pathogenic. -

Glioma susceptibility 2

Pathogenic:2

Dec 09, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdomyosarcoma

Pathogenic:1

Sep 01, 2020

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C2931456:Familial prostate cancer;C3551915:Familial meningioma;CN072330:Cowden syndrome 1

Pathogenic:1

Jun 08, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastric cancer

Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Malignant tumor of prostate;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1

Pathogenic:1

Mar 15, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Macrocephaly-autism syndrome;CN072330:Cowden syndrome 1

Pathogenic:1

Aug 11, 2023

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ovarian neoplasm

Pathogenic:1

Dec 01, 2018

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Abnormal cardiovascular system morphology

Pathogenic:1

MAGI's Lab - Research, MAGI Group

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Uncertain

0.95

Vest4

0.97

GERP RS

5.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over