rs121909218

Positions:

• chr10-87933145-G-A
• chr10-87933145-G-C
• chr10-87933145-G-T

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.386G>A​(p.Gly129Glu) 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. G129R) has been classified as Likely 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:7
• 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 19 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr10-87933144-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.992
• PP5: Variant 10-87933145-G-A is Pathogenic according to our data. Variant chr10-87933145-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87933145-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.386G>A	p.Gly129Glu	missense_variant	5/9	ENST00000371953.8
PTEN	NM_001304717.5	c.905G>A	p.Gly302Glu	missense_variant	6/10
PTEN	NM_001304718.2	c.-365G>A		5_prime_UTR_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.386G>A	p.Gly129Glu	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/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:2

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, 10051603, 24766807]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 02, 1999	- -

PTEN hamartoma tumor syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Herman Laboratory, Nationwide Children's Hospital	Mar 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly129 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9256433, 17928923, 22469695, 25527629, 28497778). 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: 10698713, 12075083, 12208743, 21828076, 22962422, 29706350, 29785012). 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: 7812). This missense change has been observed in individuals with clinical features of PTEN hamartoma tumor syndrome (PMID: 9140396, 23399955). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 129 of the PTEN protein (p.Gly129Glu). -

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

Jan 31, 2022

Published functional studies demonstrate a damaging effect: loss of lipid phosphatase activity and inability to regulate the PI-3K pathway (Leslie 2000, Rodriguez-Escudero 2011, He 2012, Mighell 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26827793, 9600246, 21659347, 9811831, 10698713, 21828076, 22962422, 29706350, 9140396, 23399955, 19457929, 24475377, 10051603, 19915616, 9616126, 12208743, 11230179, 12414663, 12075083, 9467011, 10923032, 27477328, 28526761, 32003824) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2018

The p.G129E pathogenic mutation (also known as c.386G>A), located in coding exon 5 of the PTEN gene, results from a G to A substitution at nucleotide position 386. The glycine at codon 129 is replaced by glutamic acid, an amino acid with similar properties. This mutation has been reported in multiple Cowden syndrome and Cowden syndrome-like families (Liaw D et al. Nat. Genet. 1997 May; 16(1):64-7; Ngeow J et al. Gastroenterology 2013 Jun; 144(7):1402-9, 1409.e1-5; Pilarski R et al. J. Med. Genet. 2011 Aug;48(8):505-12). This mutation is located in the P-catalytic loop of the PTEN protein and has been shown to result in a fully inactive protein by in vivo functional analysis using a heterologous yeast reconstitution system (Rodríguez-Escudero I et al. Hum. Mol. Genet. 2011 Nov; 20(21):4132-42). Multiple functional studies have also shown that this mutation leads to loss of lipid phosphatase activity and compromised dephosphorylation of active AKT, both of which are crucial to its tumor suppressor function (He X et al. J. Clin. Endocrinol. Metab. 2012 Nov; 97(11):E2179-87; Kandasamy K et al. Cancer Res. 2002 Sep; 62(17):4929-37; Ramaswamy S et al. Proc. Natl. Acad. Sci. U.S.A. 1999 Mar; 96(5):2110-5; Leslie NR et al. Biochem. J. 2000 Mar;346 Pt 3:827-33). Based on the available evidence, this variant is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
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	Pathogenic	1.0	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.92		Gain of ubiquitination at K128 (P = 0.0416);
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
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: rs121909218; hg19: chr10-89692902; COSMIC: COSV64291659;