rs121909241

Positions:

• chr10-87933154-G-A
• chr10-87933154-G-C
• chr10-87933154-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM6 PP2 PS4 PS3

This summary comes from the ClinGen Evidence Repository: PTEN c.395G>A (p.Gly132Asp) meets criteria to be classified as 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 29706350, PMID 32350270)PS4: Probands with phenotype specificity score of 4-15.5 (PMID 25288137, PMID 23335809, PMID 23470840, internal laboratory contributor(s) SCV000279163)PM2: Absent in large sequenced populations (PMID 27535533)PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000279163)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/CA000444/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_001304718.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic reviewed by expert panel P:12 U:1
• 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 13 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.
• PM6: 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/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.395G>A	p.Gly132Asp	missense_variant	5/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304718.2	c.-356G>A		5_prime_UTR_premature_start_codon_gain_variant	4/9		NP_001291647.1
PTEN	NM_001304717.5	c.914G>A	p.Gly305Asp	missense_variant	6/10		NP_001291646.4
PTEN	NM_001304718.2	c.-356G>A		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>A	p.Gly132Asp	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

Submissions summary: Pathogenic:12 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2023	Published functional studies demonstrate a damaging effect: loss of 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: 25288137, 26919320, 23470840, 23335809, 22266152, 15120218, 20600018, 27477328, 27514801, 32037394, 33509259, 31594918, 19457929, 24475377, 27535533, 32350270, 33309985, 29706350) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	PTEN: PS2, PS4, PM1, PM2, PM5, PS3:Moderate, PP2, PP3, PP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 17, 2023	The PTEN c.395G>A (p.Gly132Asp) variant has been reported in the published literature in individuals affected with PTEN Hamartoma Tumor syndrome (PMID: 15120218 (2004), 20600018 (2010), 23335809 (2013), and 25527629 (2015)) and autism spectrum disorder (PMID: 25288137 (2015)). This variant has also been reported to have a deleterious effect on PTEN protein function (PMID: 29706350 (2018), 32350270 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Nov 29, 2021	This variant has previously been reported in patients with PTEN hamartoma tumor syndrome (PHTS), which includes Cowden syndrome (CS, MIM: 158350) and Bannayan-Riley-Ruvalcaba syndrome (BRRS), all of which have significant clinical overlap (PMID: 15120218, PMID: 22266152, PMID: 23470840, PMID: 25288137). -

PTEN hamartoma tumor syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 12, 2023	Experimental studies have shown that this missense change affects PTEN function (PMID: 29706350). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly132 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16752378, 16773562, 21659347). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 132 of the PTEN protein (p.Gly132Asp). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTEN protein function. ClinVar contains an entry for this variant (Variation ID: 92822). This missense change has been observed in individuals with PTEN hamartoma tumor syndrome (PMID: 20600018, 22266152, 23335809, 23470840, 27477328). This variant is not present in population databases (gnomAD no frequency). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 11, 2020	Variant summary: PTEN c.395G>A (p.Gly132Asp) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain (IPR003595) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251384 control chromosomes (gnomAD). c.395G>A has been reported in the literature in individuals affected with PTEN Hamartoma Tumor Syndrome as well as Cowden syndrome (example: Bubien_2014, Busch_2013, Chen_2017, Derrey_2004, Heald_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cite the variant as likely pathogenic/pathogenic or uncertain significance. An expert panel (ClinGen PTEN Variant Curation Expert Panel) also cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Jun 18, 2020	PTEN c.395G>A (p.Gly132Asp) meets criteria to be classified as 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 29706350, PMID 32350270) PS4: Probands with phenotype specificity score of 4-15.5 (PMID 25288137, PMID 23335809, PMID 23470840, internal laboratory contributor(s) SCV000279163) PM2: Absent in large sequenced populations (PMID 27535533) PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000279163) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid (exon 5). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region) (DSPc - dual specificity phosphatase, catalytic domain; Decipher, PDB). (P) 0702 - Comparable variants have strong previous evidence for pathogenicity. Multiple alternative change at the same residue, to valine, alanine, serine and phenylalanine, have previously been reported as pathogenic in patients with PTEN-related syndromes (ClinVar, HGMD, LOVD, PMID: 16752378, PMID: 17526801, PMID: 29806868, PMID: 27489861). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in multiple patients with PTEN-related syndromes (ClinVar, HGMD, LOVD, PMID: 23335809, PMID: 23470840, PMID: 25288137, PMID: 31594918). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Cowden syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Feb 11, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 27, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22266152, 21194675, 23335809, 16752378, 16773562, 17526801]. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The p.G132D variant (also known as c.395G>A), located in coding exon 5 of the PTEN gene, results from a G to A substitution at nucleotide position 395. The glycine at codon 132 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported 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). 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 05;102(5):943-955). 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 was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Glioma susceptibility 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 25, 2023

- -

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	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.2	H
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.3	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		Gain of ubiquitination at K128 (P = 0.0416);
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		5.2
Varity_R		1.0
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: COSV64288421;