10-87933223-A-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000314.8(PTEN):c.464A>G(p.Tyr155Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y155H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:16 U:1
• Conservation: PhyloP100: 8.88

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 19 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000314.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-87933222-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, PTEN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 10-87933223-A-G is Pathogenic according to our data. Variant chr10-87933223-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 404168.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr10-87933223-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.464A>G	p.Tyr155Cys	missense_variant	5/9	ENST00000371953.8
PTEN	NM_001304717.5	c.983A>G	p.Tyr328Cys	missense_variant	6/10
PTEN	NM_001304718.2	c.-287A>G		5_prime_UTR_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.464A>G	p.Tyr155Cys	missense_variant	5/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460882 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726820

Gnomad4 AFR exome AF: 0.0000299

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.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 27, 2023	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with conditions associated with PTEN-hamartoma tumor syndrome (PMID: 23399955 (2013), 21194675 (2011), 27531073 (2016), 29706646 (2018), 32664367 (2020), 33083010 (2020), 33088792 (2020), 12614768 (2003), 23335809 (2013)). Published functional studies showed that this variant causes reduced phosphatase activity compared to the wild type protein (PMID: 10866302 (2000), 21828076 (2011)). 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	-	- -

PTEN hamartoma tumor syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	University Health Network, Princess Margaret Cancer Centre	-	This variant c.464 A>G is not present in population databases. It has been reported in individuals affected with PHTS (Bubien 2013, Gicquel 2003, Ngeow 2013, Andres-Pons 2007). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 155 of the PTEN protein (p.Tyr155Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Cowden syndrome or PTEN hamartoma tumor syndrome (PMID: 12614768, 17942903, 23335809, 23399955, 27531073). ClinVar contains an entry for this variant (Variation ID: 404168). 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: 10866302, 17942903, 21828076). This variant disrupts the p.Tyr155 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been observed in individuals with PTEN-related conditions (PMID: 30181857), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Nov 22, 2019	PTEN c.464A>G (p.Tyr155Cys) 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 21828076, 10866302, 29706350) PS4: Probands with phenotype specificity score of 4-15.5 (PMID 23399955, internal laboratory contributors SCV000579967.3, ClinVar Organization ID: 19864) PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID: 26957) PM2: Absent in large sequenced populations (PMID 27535533). 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. -

Cowden syndrome 1 Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 02, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 28, 2023	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302, 11051241, 27829222]. 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: 12614768]. -
Uncertain significance, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Sep 01, 2017	this variant was indentified in an individual with malformations of cortical development -

PTEN hamartoma tumor syndromes Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Jan 14, 2019

The c.464A>G (p.Tyr155Cys) variant in the PTEN gene has been reported in multiple individuals with Cowden's disease or PTEN hamartoma tumor syndrome (PMID 12614768, 17942903, 19265751, 23335809, 23399955, 27531073). This variant is absent from large databases of genetic variation in the general population. In vitro phosphatase activity assay demonstrated that the activity of the mutant protein is equivalent to a null allele (PMID 10866302). Multiple lines of algorithms predict deleterious effect of the p.Tyr155Cys change. Therefore, the c c.464A>G (p.Tyr155Cys) variant in the PTEN gene is classified as likely pathogenic. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Papillary tumor of the pineal region Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2021

The p.Y155C pathogenic mutation (also known as c.464A>G), located in coding exon 5 of the PTEN gene, results from an A to G substitution at nucleotide position 464. The tyrosine at codon 155 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in numerous individuals with personal and/or family history consistent with PTEN Hamartoma Tumor Syndrome (Tan MH et al. Am. J. Hum. Genet. 2011 Jan; 88(1):42-56; Gicquel JJ et al. Am. J. Ophthalmol. 2003 Mar; 135(3):400-2; Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; Ngeow J et al. Gastroenterology, 2013 Jun;144:1402-9, 1409.e1-5; Nizialek E et al. Eur. J. Hum. Genet. 2015 Nov;23(11):1538-43; Driessen GJ et al. J. Allergy Clin. Immunol., 2016 12;138:1744-1747.e5; Wiszniewski W et al. Eur J Hum Genet, 2018 08;26:1121-1131; Szabo Yamashita T et al. Eur Thyroid J, 2020 Sep;9:243-246; Plamper M et al. Cells, 2020 07;9; Kim RH et al. NPJ Genom Med, 2020 Sep;5:40; Ambry internal data). In a yeast functional assay, this variant demonstrated loss of in vivo phosphatase activity (Rodríguez-Escudero I et al. Hum. Mol. Genet. 2011 Nov; 20(21):4132-42). 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)). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

Pathogenic, criteria provided, single submitter

clinical testing

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

May 25, 2023

- -

Glioma susceptibility 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-8.7	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.86		Loss of phosphorylation at Y155 (P = 0.0194);
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.98
gMVP		0.99

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: rs1060500126; hg19: chr10-89692980; COSMIC: COSV64291751;