rs587781273

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM2PP2BP6_Very_Strong

The NM_000314.8(PTEN):c.1078A>G(p.Ser360Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000683 in 1,609,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S360T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

PTEN
NM_000314.8 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:11B:2

Conservation

PhyloP100: 8.68

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, PTEN

BP6

Variant 10-87965338-A-G is Benign according to our data. Variant chr10-87965338-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 140777.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PTEN	NM_000314.8 linkuse as main transcript	c.1078A>G	p.Ser360Gly	missense_variant	9/9	ENST00000371953.8
PTEN	NM_001304717.5 linkuse as main transcript	c.1597A>G	p.Ser533Gly	missense_variant	10/10
PTEN	NM_001304718.2 linkuse as main transcript	c.487A>G	p.Ser163Gly	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8 linkuse as main transcript	c.1078A>G	p.Ser360Gly	missense_variant	9/9	1	NM_000314.8	P1	P60484-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152226

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000409

AC:

AN:

244340

Hom.:

AF XY:

0.00

AC XY:

AN XY:

132062

show subpopulations

Gnomad AFR exome

AF:

0.0000641

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1457526

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

724696

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000631

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74380

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:11Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PTEN: PP2, BS1:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate protein stability similar to wildtype (Matreyek 2018, Mighell 2018); This variant is associated with the following publications: (PMID: 32185379, 29706350, 29785012) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 05, 2021	The PTEN c.1078A>G; p.Ser360Gly variant (rs587781273), to our knowledge, is not reported in an individual with PTEN hamartoma tumor syndrome, but is reported in an individual with sepsis (Borghesi 2020). The variant is listed in the ClinVar database (Variation ID: 140777) and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 360 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.441). References: Borghesi A et al. Whole-exome sequencing for the identification of rare variants in primary immunodeficiency genes in children with sepsis - a prospective population-based cohort study. Clin Infect Dis. 2020 Mar 18;71(10):e614-23. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 10, 2023	The frequency of this variant in the general population, 0.0000073 (2/275738 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. The variant has been reported in individuals with breast cancer (PMIDs: 35264596 (2022) and 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PTEN)) and in an individual with sepsis (PMID: 32185379 (2020)). A humanized, yeast-based functional study showed that this variant maintains the lipid phosphatase activity of the PTEN protein (PMID: 29706350 (2018)). Based on the available information, we are unable to determine the clinical significance of this variant. -

PTEN hamartoma tumor syndrome

Uncertain:3Benign:1

Likely benign, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Oct 11, 2023	NM_000314.8(PTEN):c.1078A>G (p.Ser360Gly) meets criteria to be classified as likely benign 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). 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. BS1_P: To be applied for variants with filtering allele frequency of 0.0000043 up to 0.000043 (0.00043% up to 0.0043%) in gnomAD. Popmax FAF of this variant=0.00001171. BP4: REVEL score < 0.5 (score of this variant=0.441). Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 2 benign supporting and 1 pathogenic supporting codes get (-1*2) + 1 points; total is –1 (likely benign). -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 01, 2023	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 360 of the PTEN protein (p.Ser360Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with predominantly antibody disorders and breast and/or ovarian cancer (PMID: 32185379, 35264596). ClinVar contains an entry for this variant (Variation ID: 140777). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt PTEN function with a negative predictive value of 95%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 14, 2023	This missense variant replaces serine with glycine at codon 360 of the PTEN protein. A humanized, yeast-based functional study measuring lipid phosphatase activity demonstrated that the variant behaves similar wild-type PTEN in this assay (PMID: 29706350). This variant has not been reported in individuals affected with hereditary cancer 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Cowden syndrome 1

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 20, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 04, 2015	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 24, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 10, 2022	This missense variant replaces serine with glycine at codon 360 of the PTEN protein. A humanized, yeast-based functional study measuring lipid phosphatase activity demonstrated that the variant behaves similar wild-type PTEN in this assay (PMID: 29706350). This variant has not been reported in individuals affected with hereditary cancer 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Uncertain

0.060

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.53

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.44

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

0.97

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.44

Sift

Benign

0.085

Sift4G

Benign

0.24

Polyphen

0.98

Vest4

0.44

MutPred

0.15

Loss of phosphorylation at S360 (P = 0.0124);

MVP

0.87

MPC

2.0

ClinPred

0.40

GERP RS

5.3

Varity_R

0.38

gMVP

0.34

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