rs398123321

Variant names:

• chr10-87933090-T-C
• rs398123321
• NM_000314.8:c.331T>C

Your query was ambiguous. Multiple possible variants found:

• chr10-87933090-T-C
• chr10-87933090-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP2 PS3 PS4_Moderate PM2

This summary comes from the ClinGen Evidence Repository: PTEN c.331T>C (p.Trp111Arg) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 29785012, 29706350)PM2: Absent in large sequenced populations (PMID 27535533).PS4_M: Probands with phenotype specificity score of 2-3.5. (internal laboratory contributor(s) ClinVar Organization ID: 61756, ClinVar Organization ID: 19864)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000401/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 7.61
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• Cowden syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• PTEN hamartoma tumor syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• macrocephaly-autism syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leiomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bannayan-Riley-Ruvalcaba syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lhermitte-Duclos disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Proteus-like syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glioma susceptibility 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.331T>C	p.Trp111Arg	missense_variant	Exon 5 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.850T>C	p.Trp284Arg	missense_variant	Exon 6 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.-420T>C		5_prime_UTR_variant	Exon 4 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.331T>C	p.Trp111Arg	missense_variant	Exon 5 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:2

Jul 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 111 of the PTEN protein (p.Trp111Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with PTEN-related conditions (PMID: 1147684, 35102303; Invitae). ClinVar contains an entry for this variant (Variation ID: 92820). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 29706350, 29785012). For these reasons, this variant has been classified as Pathogenic. -

Jun 04, 2021

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

PTEN c.331T>C (p.Trp111Arg) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3: Phosphatase activity <50% of wild type (PMID 29785012, 29706350) PM2: Absent in large sequenced populations (PMID 27535533). PS4_M: Probands with phenotype specificity score of 2-3.5. (internal laboratory contributor(s) ClinVar Organization ID: 61756, ClinVar Organization ID: 19864) PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. -

not provided Pathogenic:2

Jul 25, 2012

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: significantly reduced phosphatase activity (Mighell et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with features overlapping Proteus syndrome and PTEN Hamartoma Tumor syndrome in published literature, and also observed in patients with a personal history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx (Zhou et al., 2001); This variant is associated with the following publications: (PMID: 23757202, 16704655, 12938083, 12471211, 29785012, 29706350, 29416795, 11476841, 24475377) -

Cowden syndrome 1 Pathogenic:1

Jan 13, 2022

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PTEN c.331T>C variant meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome (PHTS) with an autosomal dominant inheritance, following ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2 (https://www.clinicalgenome.org/affiliation/50012). Published functional assays have demonstrated that this variant significantly compromises the phosphatase activity of PTEN (PMID 29785012; 29706350) (PS3). This substitution is absent in large-scale general population reference sequencing datasets (PMID 32461654) (PM2). PTEN is defined by the PTEN Expert Panel as a gene with a low rate of benign missense variation, in which missense variants are a common mechanism of disease (PP2). In silico tools support that this missense variant has a deleterious effect (PP3). This variant was identified in a patient from our unit who met the consensus clinical diagnostic criteria for an operational diagnosis of Cowden syndrome (PMID 24136893; Rofes et al. 2022, submitted manuscript). The Cleveland Clinic (CC) score in this patient was >30 (PMID 21194675) (PS4_Supporting). In addition, this variant was previously reported in an individual diagnosed with Proteus syndrome, a genetic condition that also belongs to PHTS spectrum (PMID 11476841). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 31, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W111R pathogenic mutation (also known as c.331T>C), located in coding exon 5 of the PTEN gene, results from a T to C substitution at nucleotide position 331. The tryptophan at codon 111 is replaced by arginine, an amino acid with dissimilar properties. This variant was identified in an individual who met clinical diagnostic criteria for PTEN hamartoma tumor syndrome (Ambry internal data). This variant was also identified in a patient with Proteus syndrome, but no details on clinical features were reported (Zhou X et al. Lancet, 2001 Jul;358:210-1). In a high-throughput assay measuring lipid phosphatase activity, this variant demonstrated deficient function (Mighell TL et al. Am. J. Hum. Genet., 2018 05;102:943-955). In another high-throughput assay measuring intracellular protein abundance, this variant demonstrated low protein abundance (Matreyek KA et al. Nat. Genet., 2018 06;50:874-882). Based on an internal structural analysis using published crystal structures, this variant is moderately destabilizing to the structure of the phosphatase catalytic domain of PTEN (Ambry internal data; Georgescu MM et al. Cancer Res., 2000 Dec;60:7033-8; Lee CU et al. Angew. Chem. Int. Ed. Engl., 2015 Nov;54:13796-800). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.6
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.012	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.93	P
Vest4		0.96
MutPred		0.90		Gain of disorder (P = 0.003);
MVP		0.98
MPC		3.1
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs398123321; hg19: chr10-89692847; COSMIC: COSV64290246;