rs587779992

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: PTEN c.-798G>C (NC_000010.10:g.89623428G>C) 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).No criteria currently apply to this variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000581/MONDO:0017623/003

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

PTEN
NM_000314.8 5_prime_UTR

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:3B:3

Conservation

PhyloP100: 2.88

Publications

3 publications found

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:

KLLN (HGNC:37212): (killin, p53 regulated DNA replication inhibitor) The protein encoded by this intronless gene is found in the nucleus, where it can inhibit DNA synthesis and promote S phase arrest coupled to apoptosis. The expression of this DNA binding protein is upregulated by transcription factor p53. [provided by RefSeq, Dec 2012]

KLLN Gene-Disease associations (from GenCC):

Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cowden syndrome 4
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

KLLN links:

MLDHR (HGNC:55481):

MLDHR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8 link	c.-799G>C		5_prime_UTR_variant	Exon 1 of 9	ENST00000371953.8	NP_000305.3
KLLN	NM_001126049.2 link	c.-1184C>G		upstream_gene_variant		ENST00000445946.5	NP_001119521.1	B2CW77

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PTEN	ENST00000371953.8 link	c.-799G>C	5_prime_UTR_variant	Exon 1 of 9	1	NM_000314.8	ENSP00000361021.3	P60484-1
KLLN	ENST00000445946.5 link	c.-1184C>G	upstream_gene_variant		6	NM_001126049.2	ENSP00000392204.2	B2CW77
MLDHR	ENST00000692337.1 link	c.*17G>C	downstream_gene_variant				ENSP00000509326.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.0000497

AC:

AN:

241312

Hom.:

Cov.:

AF XY:

0.0000653

AC XY:

AN XY:

122574

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

6882

American (AMR)

AF:

0.00

AC:

AN:

7236

Ashkenazi Jewish (ASJ)

AF:

0.00101

AC:

AN:

8948

East Asian (EAS)

AF:

0.00

AC:

AN:

22642

South Asian (SAS)

AF:

0.00

AC:

AN:

3002

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20750

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1268

European-Non Finnish (NFE)

AF:

0.0000129

AC:

AN:

154638

Other (OTH)

AF:

0.0000627

AC:

AN:

15946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67978

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome

Pathogenic:1Uncertain:1Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 18, 2020

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

PTEN c.-798G>C (NC_000010.10:g.89623428G>C) 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). No criteria currently apply to this variant. -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Dec 07, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PTEN c.-799G>C affects a conserved nucleotide that is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 2.6e-05 in 152060 control chromosomes in the gnomAD database (v3.1 genomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.-799G>C (aka c.-798G>C), has been reported in the literature in an individual affected with Cowden Syndrome (Teresi_2007, Nizialek_2015). However, these data do not allow clear conclusions about variant significance. One publication also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant didn't affect in vitro protein binding to the PTEN promoter DNA segment, did not alter mRNA expression in transfected cells, and no difference in PTEN protein level was observed compared to the WT in patient derived lymphoblastoid cell lines (Teresi_2007). Four submitters, including an expert panel (ClinGen PTEN Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (n=2; including the expert panel), likely benign (n=1), and benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided

Uncertain:1

Mar 04, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in at least one patient with Cowden syndrome and was absent in 186 controls (PMID: 17847000, 25669429); Functional studies did not identify any transcriptional or translational modifications affecting PTEN protein expression (PMID: 17847000); No data available from control populations to assess the frequency of this variant; Also known as c.-798G>C; This variant is associated with the following publications: (PMID: 23825907, 23315997, 25669429, 17847000) -

Hereditary cancer-predisposing syndrome

Benign:1

Dec 13, 2013

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

2.9

PromoterAI

0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=283/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over