10-87952135-T-G

Position:

• chr10-87952135-T-G

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000314.8(PTEN):​c.510T>G​(p.Ser170Arg) variant causes a missense change involving the alteration of a non-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 Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S170?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.79

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 23 ACMG points.

• PS1: Transcript NM_000314.8 (PTEN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a helix (size 15) in uniprot entity PTEN_HUMAN there are 13 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 chr10-87952135-T-R 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, 0.99
• PP5: Variant 10-87952135-T-G is Pathogenic according to our data. Variant chr10-87952135-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 825458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87952135-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.510T>G	p.Ser170Arg	missense_variant	6/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1029T>G	p.Ser343Arg	missense_variant	7/10		NP_001291646.4
PTEN	NM_001304718.2	c.-82T>G		5_prime_UTR_variant	6/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.510T>G	p.Ser170Arg	missense_variant	6/9	1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Sep 28, 2023

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302, 9256433]. 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: 17526800, 9241266, 10400993]. -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 19, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 170 of the PTEN protein (p.Ser170Arg). This missense change has been observed in individual(s) with Cowden disease (PMID: 20712882). ClinVar contains an entry for this variant (Variation ID: 825458). 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. This variant disrupts the p.Ser170 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10400993, 20712882, 21194675, 21659347, 23117110). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Mar 31, 2022

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 PTEN-hamartoma tumor syndrome diseases including Cowden syndrome (PMID: 20712882 (2010)) and Bannayan–Riley–Ruvalcaba syndrome (PMID: 29444762 (2018)). The same amino acid change (p.Ser170Arg), resulting from a different nucleotide change (c.510T>A) is classified as pathogenic. 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2019

The p.S170R pathogenic mutation (also known as c.510T>G), located in coding exon 6 of the PTEN gene, results from a T to G substitution at nucleotide position 510. The serine at codon 170 is replaced by arginine, an amino acid with dissimilar properties. This variant has been identified in individuals suspected of having PTEN hamartoma tumor syndrome (PHTS) (Banneau G et al. Breast Cancer Res., 2010 Aug;12:R63; Ambry internal data). It was also seen in a proband with Bannayan-Riley-Ruvalcaba syndrome, as well as in their affected family members (Ghusayni R et al. 2018 Epileptic Disord. 2018 Feb;20(1):30-34). Another alteration (c.510T>A) with the same amino acid change (p.S170R) was reported in individuals who met clinical diagnostic criteria for PHTS and was reported to segregate with disease in three different families (Marsh DJ et al. Nat. Genet., 1997 Aug;16:333-4; de Leon MP et al. Dig Liver Dis, 2013 Jan;45:75-8; Lachlan KL et al. J. Med. Genet., 2007 Sep;44:579-85; Crucianelli F et al. Epigenetics, 2014 Oct;9:1431-8). The phosphatase activity of p.S170R was shown to be significantly reduced compared to wild type PTEN in several studies (Myers MP et al. Proc. Natl. Acad. Sci. U.S.A., 1997 Aug;94:9052-7; Han SY et al. Cancer Res., 2000 Jun;60:3147-5; Andrés-Pons A et al. Cancer Res., 2007 Oct;67:9731-9; Rodríguez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42). Based on an internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lee CU et al. Angew. Chem. Int. Ed. Engl., 2015 Nov;54:13796-800). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.90		Gain of MoRF binding (P = 0.0159);
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
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: rs121909221; hg19: chr10-89711892; COSMIC: COSV64295950; COSMIC: COSV64295950;