10-87933154-G-T

Position:

• chr10-87933154-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001304718.2(PTEN):​c.-356G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_001304718.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.53

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 10-87933154-G-T is Pathogenic according to our data. Variant chr10-87933154-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87933154-G-T is described in Lovd as [Pathogenic]. Variant chr10-87933154-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.395G>T	p.Gly132Val	missense_variant	5/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304718.2	c.-356G>T		5_prime_UTR_premature_start_codon_gain_variant	4/9		NP_001291647.1
PTEN	NM_001304717.5	c.914G>T	p.Gly305Val	missense_variant	6/10		NP_001291646.4
PTEN	NM_001304718.2	c.-356G>T		5_prime_UTR_variant	4/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.395G>T	p.Gly132Val	missense_variant	5/9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2006	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 27, 2023	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16752378, 16773562, 21194675]. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	PTEN: PM1, PM2, PM5, PS4:Moderate, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2022	Published functional studies demonstrate a damaging effect: significantly reduced lipid 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; This variant is associated with the following publications: (PMID: 10923032, 10096247, 16752378, 23161105, 9256433, 26800850, 27221918, 21659347, 16773562, 27059323, 30787465, 24475377, 19457929, 29706350, 35227301, 32157856) -

PTEN-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 2023

The PTEN c.395G>T variant is predicted to result in the amino acid substitution p.Gly132Val. This variant was reported in multiple unrelated individuals with PTEN hamartoma tumor syndrome, including at least one de novo case (Tekin et al. 2006. PubMed ID: 16752378; Sarquis et al. 2006. PubMed ID: 16773562; Pilarski et al. 2011. PubMed ID: 21659347; Table S1, Pena-Couso et al. 2022. PubMed ID: 35227301). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 21, 2023

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 132 of the PTEN protein (p.Gly132Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pediatric PTEN hamartoma tumor syndrome, with unusual phenotypic manifestations and Cowden syndrome (PMID: 16752378, 16773562, 21659347; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7852). 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). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2023

The p.G132V pathogenic mutation (also known as c.395G>T), located in coding exon 5 of the PTEN gene, results from a G to T substitution at nucleotide position 395. The glycine at codon 132 is replaced by valine, an amino acid with dissimilar properties. This variant has been described in multiple individuals with a clinical diagnosis of Cowden syndrome (Ambry internal data; Sarquis MS et al. Am J Hum Genet, 2006 Jul;79:23-30; Tekin M et al. Am. J. Med. Genet. A 2006 Jul; 140(13):1472-5). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). Another alteration at the same codon, p.G132D (c.395G>A), has been detected in several individuals that either met clinical criteria for PTEN hamartoma tumor syndrome (PHTS) or had features consistent with PHTS (Heindl M et al. Gastroenterology, 2012 May;142:1093-1096.e6; Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; Busch RM et al. Genet. Med., 2013 Jul;15:548-53; Frazier TW et al. Mol. Psychiatry, 2015 Sep;20:1132-8; Chen HH et al. J. Allergy Clin. Immunol., 2017 Feb;139:607-620.e15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). 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. -

Glioma susceptibility 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.98		Loss of catalytic residue at V133 (P = 0.0811);
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		1.0

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: rs121909241; hg19: chr10-89692911; COSMIC: COSV64293854;