10-87933234-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.475A>G(p.Arg159Gly) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R159S) 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:5
• Conservation: PhyloP100: 3.05

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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 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 chr10-87933236-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375959.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant where missense usually causes diseases, PTEN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 10-87933234-A-G is Pathogenic according to our data. Variant chr10-87933234-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87933234-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.475A>G	p.Arg159Gly	missense_variant	5/9	ENST00000371953.8
PTEN	NM_001304717.5	c.994A>G	p.Arg332Gly	missense_variant	6/10
PTEN	NM_001304718.2	c.-276A>G		5_prime_UTR_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.475A>G	p.Arg159Gly	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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 03, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2022	Not observed at significant frequency 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: 24475377, 21194675, 29785012, 10555148, 21828076, 17942903, 31594918, 29706350) -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 11, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PTEN function (PMID: 17942903). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 186094). This missense change has been observed in individual(s) with clinical features of Cowden syndrome (PMID: 21194675, 31594918; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 159 of the PTEN protein (p.Arg159Gly). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The p.R159G variant (also known as c.475A>G), located in coding exon 5 of the PTEN gene, results from an A to G substitution at nucleotide position 475. The arginine at codon 159 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in individuals with features of Cowden syndrome (Tan MH et al. Am J Hum Genet, 2011 Jan;88:42-56; Busch RM et al. Transl Psychiatry, 2019 Oct;9:253). Yeast studies have indicated that this alteration compromises PTEN protein function (Andrés-Pons A, Cancer Res. 2007 Oct; 67(20):9731-9). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). However, this variant demonstrated wild type-like intracellular protein abundance in a massively parallel functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). Based on the crystal structure for the PTEN protein, Arg159 stabilizes the conformation of the catalytic p-loop and the glycine substitution is expected to disrupt this interaction (Lee JO, Cell 1999 Oct; 99(3):323-34; Rodríguez-Escudero I, 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)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Cowden syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Dec 05, 2019

Variant summary: PTEN c.475A>G (p.Arg159Gly) results in a non-conservative amino acid change located in the phosphatase domain (IPR029023) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250998 control chromosomes (gnomAD). c.475A>G has been reported in the literature in at least one individual affected with Cowden Syndrome (CS) or CS-like phenotype (Tan_2011). These data do not allow clear conclusions about variant significance. One publication reported experimental evidence and demonstrated that the variant protein expressed in mammalian cells resulted in increased levels of Akt1 phosphorylation (Andres-Pons_2007). In addition, another variant affecting the same amino acid (R159T) was reported to be found in a patient affected with CS or CS-like phenotype (HGMD, Tan_2011), further supporting a functional role for the affected residue. One ClinVar submitter (evaluation after 2014) cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.85		Gain of ubiquitination at K163 (P = 0.0359);
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.99
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: rs786202688; hg19: chr10-89692991;