rs398123321

chr10-87933090-T-Cchr10-87933090-T-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.331T>C(p.Trp111Arg) 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. W111C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 7.61

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 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 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 chr10-87933092-G-T is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant where missense usually causes diseases, PTEN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 10-87933090-T-C is Pathogenic according to our data. Variant chr10-87933090-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92820.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr10-87933090-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.331T>C	p.Trp111Arg	missense_variant	5/9	ENST00000371953.8
PTEN	NM_001304717.5	c.850T>C	p.Trp284Arg	missense_variant	6/10
PTEN	NM_001304718.2	c.-420T>C		5_prime_UTR_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.331T>C	p.Trp111Arg	missense_variant	5/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Jun 04, 2021	PTEN c.331T>C (p.Trp111Arg) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3: Phosphatase activity <50% of wild type (PMID 29785012, 29706350) PM2: Absent in large sequenced populations (PMID 27535533). PS4_M: Probands with phenotype specificity score of 2-3.5. (internal laboratory contributor(s) ClinVar Organization ID: 61756, ClinVar Organization ID: 19864) 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 24, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects PTEN function (PMID: 29706350, 29785012). 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. ClinVar contains an entry for this variant (Variation ID: 92820). This missense change has been observed in individuals with PTEN-related conditions (PMID: 11476841; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 111 of the PTEN protein (p.Trp111Arg). -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2022	Published functional studies demonstrate a damaging effect: significantly reduced phosphatase activity (Mighell et al., 2018); 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; Observed in an individual with features overlapping Proteus syndrome and PTEN Hamartoma Tumor syndrome in published literature, and also observed in patients with a personal history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx (Zhou et al., 2001); This variant is associated with the following publications: (PMID: 23757202, 16704655, 12938083, 12471211, 29785012, 29706350, 29416795, 11476841, 24475377) -

Cowden syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Jan 13, 2022

PTEN c.331T>C variant meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome (PHTS) with an autosomal dominant inheritance, following ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2 (https://www.clinicalgenome.org/affiliation/50012). Published functional assays have demonstrated that this variant significantly compromises the phosphatase activity of PTEN (PMID 29785012; 29706350) (PS3). This substitution is absent in large-scale general population reference sequencing datasets (PMID 32461654) (PM2). PTEN is defined by the PTEN Expert Panel as a gene with a low rate of benign missense variation, in which missense variants are a common mechanism of disease (PP2). In silico tools support that this missense variant has a deleterious effect (PP3). This variant was identified in a patient from our unit who met the consensus clinical diagnostic criteria for an operational diagnosis of Cowden syndrome (PMID 24136893; Rofes et al. 2022, submitted manuscript). The Cleveland Clinic (CC) score in this patient was >30 (PMID 21194675) (PS4_Supporting). In addition, this variant was previously reported in an individual diagnosed with Proteus syndrome, a genetic condition that also belongs to PHTS spectrum (PMID 11476841). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2020

The p.W111R pathogenic mutation (also known as c.331T>C), located in coding exon 5 of the PTEN gene, results from a T to C substitution at nucleotide position 331. The tryptophan at codon 111 is replaced by arginine, an amino acid with dissimilar properties. This variant was identified in an individual who met clinical diagnostic criteria for PTEN hamartoma tumor syndrome (Ambry internal data). This variant was also identified in a patient with Proteus syndrome, but no details on clinical features were reported (Zhou X et al. Lancet, 2001 Jul;358:210-1). In a high-throughput assay measuring lipid phosphatase activity, this variant demonstrated deficient function (Mighell TL et al. Am. J. Hum. Genet., 2018 05;102:943-955). In another high-throughput assay measuring intracellular protein abundance, this variant demonstrated low protein abundance (Matreyek KA et al. Nat. Genet., 2018 06;50:874-882). Based on an internal structural analysis using published crystal structures, this variant is moderately destabilizing to the structure of the phosphatase catalytic domain of PTEN (Ambry internal data; Georgescu MM et al. Cancer Res., 2000 Dec;60:7033-8; 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	0.57
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.012	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.93	P
Vest4		0.96
MutPred		0.90		Gain of disorder (P = 0.003);
MVP		0.98
MPC		3.1
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.97
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: rs398123321; hg19: chr10-89692847; COSMIC: COSV64290246;