10-87864518-C-G

Variant names:

• chr10-87864518-C-G
• rs786204910
• NM_000314.8:c.49C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PP2 PM2_Supporting BP4 PS3_Supporting PM6

This summary comes from the ClinGen Evidence Repository: NM_000314.8(PTEN):c.49C>G (p.Gln17Glu) 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).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor)PS3_P: Other studies demonstrating lipid phosphatase activity <50% of wild-type or abnormal in vitro cellular assay or transgenic model with phenotype different from wild-type that does not meet PS3_moderate. (PMIDs: 24292679, 29706633).PM2_P: Absent in gnomADPP2: 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.BP4: REVEL score < 0.5 (score=0.498)Using the Bayesian point system (PMID:29300386) for this variant with conflicting evidence: 1 benign supporting, 1 pathogenic moderate, 3 pathogenic supporting codes get -1 + 2 + (1*3) points; total is 4 (Uncertain significance). LINK:https://erepo.genome.network/evrepo/ui/classification/CA377781947/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:3
• Conservation: PhyloP100: 7.07
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• Cowden syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• PTEN hamartoma tumor syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• macrocephaly-autism syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leiomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bannayan-Riley-Ruvalcaba syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lhermitte-Duclos disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Proteus-like syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glioma susceptibility 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.49C>G	p.Gln17Glu	missense_variant	Exon 1 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304718.2	c.-657C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9		NP_001291647.1
PTEN	NM_001304717.5	c.568C>G	p.Gln190Glu	missense_variant	Exon 2 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.-657C>G		5_prime_UTR_variant	Exon 1 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.49C>G	p.Gln17Glu	missense_variant	Exon 1 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Uncertain:2

Oct 11, 2023

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

NM_000314.8(PTEN):c.49C>G (p.Gln17Glu) 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). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor) PS3_P: Other studies demonstrating lipid phosphatase activity <50% of wild-type or abnormal in vitro cellular assay or transgenic model with phenotype different from wild-type that does not meet PS3_moderate. (PMIDs: 24292679, 29706633). PM2_P: Absent in gnomAD 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. BP4: REVEL score < 0.5 (score=0.498) Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign supporting, 1 pathogenic moderate, 3 pathogenic supporting codes get -1 + 2 + (1*3) points; total is 4 (Uncertain significance). -

Apr 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 17 of the PTEN protein (p.Gln17Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Cowden syndrome (PMID: 25669429). ClinVar contains an entry for this variant (Variation ID: 480386). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on PTEN function (PMID: 26216063, 29706633). 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 provided Pathogenic:1

Jun 16, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with Cowden or Cowden-like syndrome (Nizialek et al., 2015); Published functional studies demonstrate that Q17E modestly stimulated nuclear localization, increased the PIP3 phosphatase activity of PTEN, and could not rescue developmental defects in PTEN-Dictyostelium cells compared to the wildtype (Nguyen et al., 2014); Published functional studies in cell lines demonstrate that Q17E promotes nuclear localization of PTEN compared to wildtype (Mingo et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29706633, 25669429, 26216063, 24979808) -

Macrocephaly-autism syndrome Pathogenic:1

May 15, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Jul 25, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q17E variant (also known as c.49C>G), located in coding exon 1 of the PTEN gene, results from a C to G substitution at nucleotide position 49. The glutamine at codon 17 is replaced by glutamic acid, an amino acid with highly similar properties. This variant, referred to as c.49C>G, has been detected in a cohort of patients who met clinical diagnostic criteria for Cowden syndrome (CS) or relaxed clinical diagnostic criteria for CS-like (Nizialek EA et al. Eur. J. Hum. Genet. 2015 Nov;23:1538-43). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	0.087
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.3	L
PhyloP100		7.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.50
Sift	Benign	0.21	T
Sift4G	Benign	0.21	T
Polyphen		0.020	B
Vest4		0.53
MutPred		0.40		Loss of MoRF binding (P = 0.0755);
MVP		0.96
MPC		2.0
ClinPred		0.70	D
GERP RS		5.0
Varity_R		0.48
gMVP		0.82
Mutation Taster		=13/87	disease causing

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

Other links and lift over

dbSNP: rs786204910; hg19: chr10-89624275;