10-87957918-C-T

Position:

chr10-87957918-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP2PM2_SupportingBS3_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000314.8(PTEN):c.700C>T (p.Arg234Trp) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).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.BS3_P: Functional studies showing no damaging effect on protein function. Score of this variant = 0.106334511 (>0, WT-like range) on high throughput phosphatase assay (PMID:29706350).Using the Bayesian point system (PMID:29300386) for this variant with conflicting evidence: 1 benign supporting and 2 pathogenic supporting codes get -1 + (1*2) points; total is 1 (Uncertain significance). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000183/MONDO:0017623/003

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PTEN
NM_000314.8 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:8B:2

Conservation

PhyloP100: 4.50

Variant links:

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 links:

PTEN (HGNC:):

PTEN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP2

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8 linkuse as main transcript	c.700C>T	p.Arg234Trp	missense_variant	7/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 linkuse as main transcript	c.1219C>T	p.Arg407Trp	missense_variant	8/10		NP_001291646.4	P60484
PTEN	NM_001304718.2 linkuse as main transcript	c.109C>T	p.Arg37Trp	missense_variant	7/9		NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 linkuse as main transcript	c.700C>T	p.Arg234Trp	missense_variant	7/9	1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461720

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2024	Observed as a somatic variant in multiple tumors (PMID: 10955808, 26517354, 26197069, 25072932, 26341754); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26341754, 26517354, 10955808, 25072932, 26197069, 18626510, 29706350, 37527256, 25157968, 12085208) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 17, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 10, 2024	The PTEN c.700C>T (p.Arg234Trp) variant has not been reported as a germline variant in individuals with PTEN-related conditions in the published literature. A yeast-based functional study indicates this variant has neutral effect on PTEN lipid phosphatase activity (PMID: 29706350 (2018)). The frequency of this variant in the general population, 0.0000066 (1/152184 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 18, 2022	This missense variant replaces arginine with tryptophan at codon 234 of the PTEN protein. A functional study in a humanized yeast model has shown that this variant results in the loss of phosphatase activity of PTEN protein (PMID: 29706350). This variant has not been reported in individuals affected with PTEN-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	curation	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Apr 12, 2024	Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).For PTEN, two assays measuring activity and abundance were used. If the abundance was categorized as "wt-like" or "possibly wt-like," BS3_Supporting evidence was used. Furthermore, if the cumulative score was greater than -5, BS3_moderate evidence was used. This variant GRCh38:10:87957918:C>T was assigned evidence codes ['BS3_Supporting', 'BS1_Supporting'] and an overall classification of Likely benign -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 06, 2024	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

PTEN hamartoma tumor syndrome

Uncertain:2

Uncertain significance, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Oct 11, 2023	NM_000314.8(PTEN):c.700C>T (p.Arg234Trp) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM2: Absent in large sequenced populations (PMID 27535533). 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. BS3_P: Functional studies showing no damaging effect on protein function. Score of this variant = 0.106334511 (>0, WT-like range) on high throughput phosphatase assay (PMID:29706350). Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign supporting and 2 pathogenic supporting codes get -1 + (1*2) points; total is 1 (Uncertain significance). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 234 of the PTEN protein (p.Arg234Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 184844). 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 not expected to disrupt PTEN protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PTEN function (PMID: 29706350). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Cowden syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 12, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

D;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Uncertain

0.48

MutationAssessor

Benign

1.7

L;.

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-4.9

D;.

REVEL

Pathogenic

0.65

Sift

Benign

0.081

T;.

Sift4G

Uncertain

0.018

D;D

Polyphen

1.0

D;.

Vest4

0.83

MutPred

0.47

Loss of disorder (P = 0.0165);.;

MVP

0.82

MPC

1.3

ClinPred

0.99

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.68

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over