chr10-87933165-T-C

Position:

• chr10-87933165-T-C

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.406T>C​(p.Cys136Arg) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C136Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 7.62

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 19 ACMG points.

• PM1: In a helix (size 12) in uniprot entity PTEN_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) 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 chr10-87933166-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTEN. . Gene score misZ 3.4883 (greater than the threshold 3.09). Trascript score misZ 4.1129 (greater than threshold 3.09). GenCC has associacion of gene with Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, macrocephaly-autism syndrome, Cowden syndrome 1, Cowden disease, Proteus-like syndrome, leiomyosarcoma, activated PI3K-delta syndrome, PTEN hamartoma tumor syndrome, glioma susceptibility 2, renal cell carcinoma.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 10-87933165-T-C is Pathogenic according to our data. Variant chr10-87933165-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87933165-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.406T>C	p.Cys136Arg	missense_variant	5/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.925T>C	p.Cys309Arg	missense_variant	6/10		NP_001291646.4
PTEN	NM_001304718.2	c.-345T>C		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.406T>C	p.Cys136Arg	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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2022	Published functional studies demonstrate a damaging effect: impaired phosphatase activity, reduced PTEN protein levels and stability (He et al., 2013; Mighell et al., 2018; Matreyek et al., 2018); Not observed 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: 21659347, 31965297, 28380455, 29663862, 23335809, 32601921, 17941496, 22281088, 10848731, 27148581, 25461771, 23886400, 22520842, 15211648, 18558293, 23475934, 21343951, 20600018, 24778394, 21194675, 26376867, 31006514, 29785012, 19457929, 24475377, 29706350, 30787465, 32003824) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Cowden syndrome 1 Pathogenic:2

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: 23475934, 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, 10848731, 16773562, 21343951, 23475934]. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The PTEN c.925T>C (p.Cys309Arg) variant (also known as c.406T>C) has been reported in individuals affected with Cowden syndrome (Kubo Y et al., 2000). Experimental studies demonstrate a damaging effect: impaired phosphatase activity, reduced PTEN protein levels and stability (He X et al., 2013). The p.Cys309Arg variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The amino acid Cys at position 309 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Cys309Arg in PTEN is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

PTEN hamartoma tumor syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with ­hamartoma tumour syndrome (MONDO#0017623). Loss of function is the mechanism for null variants while missense variants have been demonstrated to exert either a loss of function or dominant-negative mechanism (GeneReviews). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In particular, PTEN-related Proteus syndrome has been described to be a highly variable disorder (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported in multiple unrelated individuals or families with PTEN hamartoma tumour syndrome (ClinVar; PMIDs: 10848731, 17941496, 21343951, 23886400, 35227301). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by segregation testing). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 136 of the PTEN protein (p.Cys136Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Cowden syndrome (PMID: 10848731, 20600018, 21343951, 21659347, 22520842, 23335809, 23886400, 24778394). ClinVar contains an entry for this variant (Variation ID: 183726). 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. Experimental studies have shown that this missense change affects PTEN function (PMID: 23475934). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 11, 2023	The p.C136R pathogenic mutation (also known as c.406T>C), located in coding exon 5 of the PTEN gene, results from a T to C substitution at nucleotide position 406. The cysteine at codon 136 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration was described as a de novo mutation in a Japanese patient with Cowden disease (Kubo Y et al. Br. J. Dermatol. 2000 Jun;142(6):1100-5). In one PTEN Hamartoma Tumor Syndrome (PHTS) family, this mutation segregated with disease in a mother and her two daughters. Clinical features included macrocephaly and thyroid lesions (follicular carcinoma and adenoma) in all three individuals, breast cancer in the mother, vertebral hemangioma in one daughter, and cortical dysplasia in the other daughter (Jenny B et al. J. Neurosurg. 2007 Oct;107(4 Suppl):307-13; Venturini G et al. Ophthalmology 2012 Apr;119(4):857-64). This mutation has also been observed in other individuals with PHTS (Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; Galatola M et al. BMC Med. Genet., 2012 Apr;13:28) including those with neurological features of PHTS such as autism and developmental delay (He X et al. Cancer Res. 2013 May;73(10):3029-40). 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 alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 21, 2022	This missense variant replaces cysteine with arginine at codon 136 of the PTEN protein. Functional studies have shown that this variant reduces protein stability and activity (PMID: 23475934, 29663862). This variant has been reported in individuals affected with Cowden syndrome/PTEN hamartoma tumour syndrome (PMID: 10848731, 20600018, 21194675, 21343951, 23335809, 23475934, 24778394, 25669429, 23886400, 26376867). It has been shown that this variant segregates with disease (PMID: 23886400). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PTEN function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Acute megakaryoblastic leukemia;C1334655:Mediastinal germ cell tumor Pathogenic:1

Pathogenic, no assertion criteria provided

research

McDonnell Genome Institute, Washington University in St. Louis

Oct 22, 2015

- -

Glioma Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PS3,PS2,PP1 -

Cowden syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 21, 2017

Variant summary: The PTEN c.406T>C (p.Cys136Arg) variant located in the Protein-tyrosine phosphatase-like domain involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 121500 control chromosomes. Multiple publications have cited the variant in affected indivdiuals diagnosed with Cowden Syndrome, BRRS, and PHTS, which was found to cosegregate with disease in multiple families. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Functional studies have demonstrated an impact of this variant on protein stability leading to increased proteasome activity which has been reported as a hallmark of human cancers. Taken together, this variant is classified as pathogenic. -

Ovarian neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Glioma susceptibility 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-9.9	D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.94		Gain of MoRF binding (P = 0.0098);
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)		0.010		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: rs786201044; hg19: chr10-89692922; COSMIC: COSV64289087;