10-87961095-C-T

Position:

• chr10-87961095-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000371953.8(PTEN):​c.1003C>T​(p.Arg335Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,168 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. R335R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PTEN ENST00000371953.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:34 U:1 O:3
• Conservation: PhyloP100: 2.10

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 33 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87961095-C-T is Pathogenic according to our data. Variant chr10-87961095-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87961095-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.1003C>T	p.Arg335Ter	stop_gained	8/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1522C>T	p.Arg508Ter	stop_gained	9/10		NP_001291646.4
PTEN	NM_001304718.2	c.412C>T	p.Arg138Ter	stop_gained	8/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.1003C>T	p.Arg335Ter	stop_gained	8/9	1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461168 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726936

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

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.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:34 Uncertain:1 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:7 Uncertain:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2007	- -
Uncertain significance, no assertion criteria provided	clinical testing	Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,	-	- -
not provided, no classification provided	literature only	GeneReviews	-	Recurrent pathogenic variants -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
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	Counsyl	Mar 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Apr 10, 2022	The c.1003C>T;p.(Arg335*) variant creates a premature translational stop signal in the PTEN gene. It is expected to result in an absent or disrupted protein product -PVS1. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID: 10749983, 10232405) - PS2. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 7833 ; PMID: 20301661; 33600059; 22595938) - PS4. This variant is not present in population databases (rs121909231- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PVS1+PS4+PM6_VeryStrong -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2021	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 at significant frequency in large population cohorts (Lek et al., 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, 31594918, 33077954) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PTEN: PVS1, PS2, PM2, PS4:Moderate, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

PTEN hamartoma tumor syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Herman Laboratory, Nationwide Children's Hospital	Mar 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 10, 2023	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, 27477328, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 24, 2023	This sequence change creates a premature translational stop signal (p.Arg335*) in the PTEN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 69 amino acid(s) of the PTEN protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hamartoma tumor syndrome (PMID: 9399897, 9467011, 10232405, 10353779, 10400993, 10749983, 11685670, 24052722). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7833). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PTEN function (PMID: 9399897, 23475934). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 29, 2020	proposed classification - variant undergoing re-assessment, contact laboratory -

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 23, 2021	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 alteration occurs at the 3' terminus of thePTEN gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 69 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration 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 alteration 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Oct 19, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 08, 2022	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, 27477328, 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. -
Pathogenic, criteria provided, single submitter	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	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. -

Macrocephaly-autism syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	May 06, 2024	PVS1, PS2, PS4, PM2 -
Pathogenic, criteria provided, single submitter	research	Cavalleri Lab, Royal College of Surgeons in Ireland	Dec 11, 2019	ACMG evidence PVS1, PS2, PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Jan 29, 2015	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. -

PTEN-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 28, 2024	The PTEN c.1003C>T variant is predicted to result in premature protein termination (p.Arg335*). This variant has been reported to be causative for Cowden syndrome, and has been observed to arise de novo in some individuals and as an inherited variant in others (See for example: referred to as 1003C>T, R334X, Lynch et al. 1997. PubMed ID: 9399897; Table S1, Busch et al. 2013. PubMed ID: 23470840; Ngeow et al. 2014. PubMed ID: 24778394; Benson et al. 2020. PubMed ID: 32238909). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic by several laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/7833/). Nonsense variants in PTEN are expected to be pathogenic. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Mar 05, 2018	- -

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

Feb 14, 2022

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Aug 10, 2020

The PTEN c.1003C>T variant is classified as Pathogenic (PVS1, PM2, PP1_Strong) -

Macrocephaly-autism syndrome;CN072330:Cowden syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 01, 2017

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 -

Cowden syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 10, 2020

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. -

Ovarian neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

Proteus-like syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2007

- -

Abnormality of the nervous system Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Cowden syndrome;C1854416:Macrocephaly-autism syndrome Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Pathogenic and reported on 01-25-2021 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A
Vest4		0.91
GERP RS		4.4

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

Other links and lift over

dbSNP: rs121909231; hg19: chr10-89720852; COSMIC: COSV64288687;