chr10-87863635-C-T

Position:

chr10-87863635-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000692337.1(ENSG00000289051):c.77C>T(p.Ser26Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 391,604 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 4/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S26A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

ENST00000692337.1 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:14

Conservation

PhyloP100: 1.69

Variant links:

Genes affected

(HGNC:):

links:

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein
PTEN	NM_000314.8 linkuse as main transcript	c.-835C>T	5_prime_UTR_variant	1/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 linkuse as main transcript	c.-315C>T	5_prime_UTR_variant	1/10		NP_001291646.4
PTEN	NM_001304718.2 linkuse as main transcript	c.-1539C>T	5_prime_UTR_variant	1/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
	ENST00000692337.1 linkuse as main transcript	c.77C>T	p.Ser26Phe	missense_variant	1/1			ENSP00000509326	P1
PTEN	ENST00000371953.8 linkuse as main transcript	c.-835C>T		5_prime_UTR_variant	1/9	1	NM_000314.8	ENSP00000361021	P1	P60484-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152082

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:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000200

AC:

AN:

239522

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

AN XY:

121686

show subpopulations

Gnomad4 AFR exome

AF:

0.000147

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:

0.000290

Gnomad4 NFE exome

AF:

0.000261

Gnomad4 OTH exome

AF:

0.0000632

GnomAD4 genome

AF:

0.000105

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74288

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:

0.0000945

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.000147

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2024	Observed in individuals meeting either 'relaxed' or classic diagnostic criteria for Cowden syndrome per the International Cowden Consortium criteria and did not show a significant association with breast cancer in a case-control study (PMID: 12844284, 17847000, 21956414, 35172517); Published functional studies did not identify any transcriptional or translational modifications affecting PTEN protein expression (PMID: 17847000); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.-834C>T; This variant is associated with the following publications: (PMID: 27187382, 21956414, 25910213, 25669429, 24778394, 21194675, 23825907, 35172517, 26229595, 12844284, 12938083, 17847000) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 30, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	- -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 19, 2022	Variant summary: PTEN c.-835C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.00011 in 144592 control chromosomes. The observed variant frequency is approximately 17.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTEN causing Cowden Syndrome phenotype (6.3e-06), suggesting that the variant is benign. c.-835C>T has been reported in the literature in individuals affected with Cowden Syndrome (e.g. Zhou_2003, Teresi_2007, Ngeow_2011, Tan_2011, Liu_2013 Ngeow_2014, Nizialek_2015). These reports do not provide unequivocal conclusions about association of the variant with Cowden Syndrome. One study (Black_2017) indicates the variant to have been observed in 10 controls, however, the nature of this cohort is not entirely clear other than stating the individuals did not have a personal history of cancer (ie, age or family history not provided). In addition, one functional study (Teresi_2007) found the variant to not have an impact on PTEN protein expression, while another functional study utilizing a yeast two-hybrid system suggested the variant causes the interaction with the associated transcription factor to be lost (Fuxman-Bass_2015). Nine ClinVar submitters (evaluation after 2014), including the ClinGen PTEN Variant Curation Expert Panel, have cited the variant, with all labs classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 22, 2020	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 10, 2013	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Apr 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 09, 2024	- -

PTEN-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 16, 2024

The PTEN c.-315C>T variant is located in the 5' untranslated region. This variant (also referred to as c.-834C>T) has been reported in at least three patients with Cowden syndrome or a Cowden syndrome-like phenotype (Teresi et al. 2007. PubMed ID: 17847000; Ngeow et al. 2011. PubMed ID: 21956414). Similar sequence variants in the PTEN promoter have been shown to disrupt gene expression and have been associated with PTEN-related disorders (Zhou et al. 2003. PubMed ID: 12844284). This variant was shown to disrupt transcription factor binding by one assay (Fuxman Bass. 2015. PubMed ID: 25910213); however, transcription factor binding and PTEN activity was unaffected in a separate analysis (Teresi et al. 2007. PubMed ID: 17847000). This variant is reported in just one of ̴ 31,000 alleles in the gnomAD database, and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127676/). At this time, we interpret this change as a variant of uncertain significance due to the absence of conclusive functional and genetic evidence. -

Cowden syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 13, 2017

- -

PTEN hamartoma tumor syndrome

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

Clingen PTEN Variant Curation Expert Panel, Clingen

Oct 20, 2020

PTEN c.-835C>T, also described as c.-834C>T (NC_000010.10:g.89623392C>T) is currently classified as a variant of uncertain significance 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). BS1_P: Allele frequency of 0.0002207 (0.02207%, 15/67980 alleles) in the European subpopulation of the gnomAD cohort, v3.1.2. (PMID 27535533) -

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

Aug 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.98

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