10-87933166-G-A

Position:

• chr10-87933166-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PS4_Supporting PS3 PS2

This summary comes from the ClinGen Evidence Repository: PTEN c.407G>A (p.C136Y) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000222113.9)PS3: Phosphatase activity <50% of wild-type OR RNA, mini-gene, or other assay shows impact on splicing. (PMID 10866302)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.PS4_P: Probands with specificity score of 1-1.5. (PMID 9735393, internal laboratory contributor(s) SCV000222113.9) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000451/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.407G>A	p.Cys136Tyr	missense_variant	5/9	ENST00000371953.8
PTEN	NM_001304717.5	c.926G>A	p.Cys309Tyr	missense_variant	6/10
PTEN	NM_001304718.2	c.-344G>A		5_prime_UTR_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.407G>A	p.Cys136Tyr	missense_variant	5/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 04, 2023	ClinVar contains an entry for this variant (Variation ID: 189406). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys136 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10848731, 20600018, 21659347, 23886400, 24778394). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PTEN function (PMID: 9735393, 10866302). 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. This missense change has been observed in individuals with Cowden syndrome (CD) and Bannayan-Riley-Ruvalcaba syndrome (PMID: 9735393, 20600018, 21194675, 21659347). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 136 of the PTEN protein (p.Cys136Tyr). -
Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Oct 18, 2017	PTEN c.407G>A (p.C136Y) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000222113.9) PS3: Phosphatase activity <50% of wild-type OR RNA, mini-gene, or other assay shows impact on splicing. (PMID 10866302) 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. PS4_P: Probands with specificity score of 1-1.5. (PMID 9735393, internal laboratory contributor(s) SCV000222113.9) -

Cowden syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Sep 27, 2023

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302]. 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: 9735393, 16773562]. -

Malignant tumor of urinary bladder Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Urology, Hospital Clinic de Barcelona

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not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 23, 2021

Published functional studies demonstrate a damaging effect: loss of phosphatase activity (Han 2000, Mighell 2018); Not observed at significant frequency in large population cohorts (Lek 2016); 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: 11668501, 16773562, 32378608, 21956414, 12938083, 17941496, 15492994, 21659347, 10866302, 21194675, 29706350, 9735393, 20600018, 19457929, 24475377, 30561760, 30736836, 30787465) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2022

The p.C136Y pathogenic mutation (also known as c.407G>A), located in coding exon 5 of the PTEN gene, results from a G to A substitution at nucleotide position 407. The cysteine at codon 136 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been reported in individuals meeting clinical criteria for PTEN Hamartoma Tumor Syndrome (PHTS)/Cowden syndrome (CS) or relaxed clinical diagnostic criteria for CS-like (Sarquis MS et al. Am. J. Hum. Genet., 2006 Jul;79:23-30; Heald B et al. Gastroenterology, 2010 Dec;139:1927-3; Ngeow J et al. J Clin Endocrinol Metab. 2011 Dec;96(12):E2063-71; Tan MH et al. Am J Hum Genet. 2011 Jan 7;88(1):42-56; Nizialek EA et al. Eur. J. Hum. Genet., 2015 Nov;23:1538-43). In addition, this variant has been determined to be the result of a de novo mutation or germline mosaicism in one family in our clinical cohort (Ambry internal data). In two separate functional studies, lipid phosphatase activity for this variant was functionally deficient (Han SY et al. Cancer Res., 2000 Jun;60:3147-51; Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). Two other alterations at the same codon, p.C136R (c.406T>C) and p.C136F (c.407G>T), have been detected in individuals with features consistent with PTEN Hamartoma Tumor Syndrome (PHTS) (Kubo Y et al. Br. J. Dermatol. 2000 Jun;142(6):1100-5; Jenny B et al. J. Neurosurg. 2007 Oct;107(4 Suppl):307-13; Venturini G et al. Ophthalmology 2012 Apr;119(4):857-64; Galatola M et al. BMC Med. Genet., 2012 Apr;13:28; Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; He X et al. Cancer Res. 2013 May;73(10):3029-40). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 amino acid position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration 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	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-8.9	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.92		Gain of MoRF binding (P = 0.0809);
MVP		0.97
MPC		2.6
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
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: rs786204859; hg19: chr10-89692923; COSMIC: COSV64288670;