rs375709098

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BS3_SupportingBP4BS1

This summary comes from the ClinGen Evidence Repository: NM_000314.8(PTEN):c.1061C>A (p.Pro354Gln) variant 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). BS1: To be applied for variants with filtering allele frequency (FAF) of 0.000043 up to 0.00056 (0.0043% up to 0.056%) in gnomAD. Popmax FAF of this variant=0.0001051.BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function. This variant: score of 0.09 (WT-like range) on high throughput phosphatase assay (PMID:29706350).BP4: REVEL score < 0.5 (score=0.497).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.Using the Bayesian point system (PMID:29300386) for this variant with conflicting evidence: 1 benign strong and 2 benign supporting = -6. 1 pathogenic supporting = 1. Total = – 5 (likely benign). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000275/MONDO:0017623/003

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

PTEN
NM_000314.8 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:15B:6

Conservation

PhyloP100: 5.59

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.

PP2

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

BP4

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

BS1

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
PTEN	NM_000314.8 linkuse as main transcript	c.1061C>A	p.Pro354Gln	missense_variant	9/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 linkuse as main transcript	c.1580C>A	p.Pro527Gln	missense_variant	10/10		NP_001291646.4
PTEN	NM_001304718.2 linkuse as main transcript	c.470C>A	p.Pro157Gln	missense_variant	9/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 linkuse as main transcript	c.1061C>A	p.Pro354Gln	missense_variant	9/9	1	NM_000314.8	ENSP00000361021	P1	P60484-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000817

AC:

AN:

244884

Hom.:

AF XY:

0.0000756

AC XY:

AN XY:

132270

show subpopulations

Gnomad AFR exome

AF:

0.000128

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:

0.000164

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000123

AC:

180

AN:

1457490

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

724668

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

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:

0.000154

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152018

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.000103

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000195

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:15Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2018	This variant is denoted PTEN c.1061C>A at the cDNA level, p.Pro354Gln (P354Q) at the protein level, and results in the change of a Proline to a Glutamine (CCG>CAG). Mester et al. (2011) reported this variant occurring in two related individuals with features of Cowden syndrome, however neither met International Cowden Syndrome Consortium diagnostic criteria. Pilarski et al. (2011) reported an additional patient with this variant identified through clinical PTEN testing. Yurgelun et al. (2015) identified this variant in an individual undergoing multi-gene cancer panel testing based on a history of a Lynch syndrome-related cancer and/or polyps; this particular individual was also found to harbor a pathogenic MSH2 variant. Lastly, this variant was observed in an individual with neuroblastoma and in an individual with a personal and family history of breast cancer (Zhang 2015, Caminsky 2016). PTEN Pro354Gln was observed at an allele frequency of 0.016% (19/122,896) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the C-terminal domain (Wang 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PTEN Pro354Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 08, 2023	In the published literature, this variant has been reported in affected individuals with breast cancer (PMID: 21343951 (2011)), suspected Lynch syndrome (PMID: 25980754 (2015)), melanoma (PMID: 31567591 (2020)), hamartoma tumor syndrome (PMID: 35931053 (2022)), and in individuals with features of Cowden syndrome (PMID: 25669429 (2015)). In a large-scale breast cancer association study, this variant was observed in breast cancer cases as well as study controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PTEN)). In addition, multiple experimental studies have shown this variant has a neutral effect on PTEN lipid phosphatase activity and protein abundance (PMIDs: 29706350 (2018), 29785012 (2018), and 32350270 (2020)). The frequency of this variant in the general population, 0.00015 (19/125384 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 28, 2022	proposed classification - variant undergoing re-assessment, contact laboratory -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 13, 2016	- -

not specified

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 22, 2024	Variant summary: PTEN c.1061C>A (p.Pro354Gln) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-05 in 244884 control chromosomes. The observed variant frequency is approximately 13.067 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTEN causing Cowden Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. c.1061C>A has been reported in the literature in sequencing studies of individuals affected with gliomas (Caldera_2011, tumor sequencing of large cell carcinomas (Karlsson_2015), PTEN Hamartoma Tumour Syndrome (Mester_2011), PTEN clinical testing cohort (Pilarski_2011), individuals meeting relaxed Cowden syndrome criteria (Tan_2011), LS clinical testing cohort (Yurgelun_2015), an unpublished case report of an individual undergoing diagnostic exome sequencing with an unrelated phenotype who's unaffected mother and brother carried the variant of interest (Tsang_2015) and as a variant that was excluded from a case control study analysis due to low penetrance (Couch_2018). At-least one co-occurrence with another pathogenic variant has been reported (MSH2 c.2047G>A, p.Gly683Arg), providing supporting evidence for a benign role (Yurgelun_2015). Additionally, the variant was reported to have wild-type range of function via a high throughput phosphatase assay (Mighell_2018). The following publications have been ascertained in the context of this evaluation (PMID: 21869887, 28418444, 26124082, 21343951, 21659347, 21194675, 25980754, 29706350). ClinVar contains an entry for this variant (Variation ID: 143020), with a likely benign classification from the Clingen PTEN Variant Curation Expert Panel. Based on the evidence outlined above, the variant was classified as likely benign. -

Cowden syndrome 1

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -

PTEN hamartoma tumor syndrome

Uncertain:1Benign:2

Likely benign, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Jun 14, 2023	NM_000314.8(PTEN):c.1061C>A (p.Pro354Gln) variant 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). BS1: To be applied for variants with filtering allele frequency (FAF) of 0.000043 up to 0.00056 (0.0043% up to 0.056%) in gnomAD. Popmax FAF of this variant=0.0001051. BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function. This variant: score of 0.09 (WT-like range) on high throughput phosphatase assay (PMID:29706350). BP4: REVEL score < 0.5 (score=0.497). 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. Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign strong and 2 benign supporting = -6. 1 pathogenic supporting = 1. Total = – 5 (likely benign). -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 16, 2023	This missense variant replaces proline with glutamine at codon 354 of the PTEN protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have reported the variant protein to be functional in a lipid phosphatase assay with a fitness score resembling those of synonymous variants (PMID: 29706350) and in protein stability/abundance assay (PMID: 29785012). This variant has been reported in individuals suspected of having Cowden syndrome (PMID: 21659347, 25669429) and Lynch syndrome (PMID: 25980754), as well as in individuals affected with breast/ovarian cancer (PMID: 21343951, 26898890), neuroblastoma (PMID: 26580448), melanoma (PMID: 31006514), and lung cancer (PMID: 26124082). This variant occurs at an elevated frequency in the general population and has been identified in 21/276260 chromosomes 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 17, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 25, 2023	This missense variant replaces proline with glutamine at codon 354 of the PTEN protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have reported the variant protein to be functional in a lipid phosphatase assay with a fitness score resembling those of synonymous variants (PMID: 29706350) and in protein stability/abundance assay (PMID: 29785012). This variant has been reported in individuals suspected of having Cowden syndrome (PMID: 21659347, 25669429) and Lynch syndrome (PMID: 25980754), as well as in individuals affected with breast/ovarian cancer (PMID: 21343951, 26898890), neuroblastoma (PMID: 26580448), melanoma (PMID: 31006514), and lung cancer (PMID: 26124082). This variant occurs at an elevated frequency in the general population and has been identified in 21/276260 chromosomes 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	clinical testing	Ambry Genetics	Feb 19, 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. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 17, 2023

- -

PTEN-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2024

The PTEN c.1061C>A variant is predicted to result in the amino acid substitution p.Pro354Gln. This variant has been documented in Cowden syndrome patients and at least one of them had breast cancer (Table S2, Tan et al. 2011. PubMed ID: 21194675; Mester et al. 2011. PubMed ID: 21343951; Table S4, Nizialek et al. 2015. PubMed ID: 25669429), in an individual with suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMedID: 25980754), in an individual with breast or ovarian cancer (Caminsky et al. 2016. PubMed ID: 26898890), in an individual with pancreatic ductal adenocarcinoma (Supplementary Table 3, Cremin et al. 2020. PubMed ID: 32255556), and in an individual with melanoma (Li et al. 2019. PubMed ID: 31567591). This variant has also been documented in patient with autism spectrum disorder (Patient 01-021 in Supplemental Table 2, Busch et al. 2019. PubMed ID: 31594918). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has interpretations ranging from benign to uncertain in ClinVar, with an expert curation panel interpreting it as likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/143020). Although we suspect this variant may be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of prostate;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 10, 2022

- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PTEN p.Pro354Gln variant was identified in 8 of 20700 proband chromosomes (frequency: 0.0004) from individuals or families with Cowden syndrome, Neuroblastoma, lynch syndrome, breast or ovarian cancer and was not identified in 222 control chromosomes from healthy individuals (Tan 2011, Zhang 2015, Pilarski 2011, Mester 2011, Yurgelun 2015, Nizialek 2015, Caminsky 2016). The variant was also identified in dbSNP (ID: rs375709098) as "With Likely pathogenic, Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl and 5 clinical laboratories), and LOVD 3.0 (2x). The variant was not identified in Cosmic, MutDB, or Zhejiang University databases. The variant was identified in control databases in 21 of 270810 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 23476 chromosomes (freq: 0.0001), European in 19 of 122896 chromosomes (freq: 0.0002); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Pro354 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.58

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.69

MetaSVM

Uncertain

0.083

MutationAssessor

Benign

0.55

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.50

Sift

Uncertain

0.027

Sift4G

Benign

0.14

Polyphen

0.47

Vest4

0.73

MVP

0.97

MPC

1.1

ClinPred

0.11

GERP RS

5.3

Varity_R

0.096

gMVP

0.28

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