rs786204940

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2BP4_ModerateBP6_Very_StrongBP7

The ENST00000692337.1(ENSG00000289051):c.75C>T(p.Ser25=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000485 in 391,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

ENST00000692337.1 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:1

Conservation

PhyloP100: 0.782

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BP6

Variant 10-87863633-C-T is Benign according to our data. Variant chr10-87863633-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 189497.Status of the report is reviewed_by_expert_panel, 3 stars.

BP7

Synonymous conserved (PhyloP=0.782 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
PTEN	NM_000314.8 linkuse as main transcript	c.-837C>T	5_prime_UTR_variant	1/9	ENST00000371953.8
PTEN	NM_001304717.5 linkuse as main transcript	c.-317C>T	5_prime_UTR_variant	1/10
PTEN	NM_001304718.2 linkuse as main transcript	c.-1541C>T	5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
	ENST00000692337.1 linkuse as main transcript	c.75C>T	p.Ser25=	synonymous_variant	1/1			P1
PTEN	ENST00000371953.8 linkuse as main transcript	c.-837C>T		5_prime_UTR_variant	1/9	1	NM_000314.8	P1	P60484-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000501

AC:

AN:

239332

Hom.:

Cov.:

AF XY:

0.0000493

AC XY:

AN XY:

121594

show subpopulations

Gnomad4 AFR exome

AF:

0.000294

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000443

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000587

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 08, 2021

Variant summary: PTEN c.-837C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 4.6e-05 in 150856 control chromosomes (gnomAD v3.1.1). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-837C>T has been reported in the literature in a Cowden syndrome study (Nizialek_2015). This report does not provide unequivocal conclusions about association of the variant with Cowden Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters including an expert panel (ClinGen PTEN Variant Curation Expert Panel) (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2023

Describes a nucleotide substitution 837 basepairs upstream of the ATG translational start site in the PTEN promoter region; Observed in individuals with features of Cowden syndrome (PMID: 25669429); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.-836C>T; This variant is associated with the following publications: (PMID: 25669429) -

PTEN hamartoma tumor syndrome

Benign:1

Likely benign, reviewed by expert panel

curation

Clingen PTEN Variant Curation Expert Panel, Clingen

Oct 11, 2023

NM_000314.8(PTEN):c.-837C>T 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_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=0.00003249 [0.003249%] in gnomAD v3. BP5: Variant found in multiple cases with alternate molecular basis for disease. (internal laboratory contributor(s)) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

Cadd

Benign

Dann

Benign

0.97

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