rs786204937

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The ENST00000693560(PTEN):c.-401G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000906 in 386,238 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

PTEN
ENST00000693560 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.568

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 links:

ENSG00000289051 (HGNC:55481):

ENSG00000289051 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 10-87863549-G-A is Benign according to our data. Variant chr10-87863549-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 189492.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
PTEN	NM_000314.8 link	c.-921G>A	upstream_gene_variant	ENST00000371953.8	NP_000305.3
KLLN	NM_001126049.2 link	c.-1062C>T	upstream_gene_variant	ENST00000445946.5	NP_001119521.1	B2CW77
PTEN	NM_001304717.5 link	c.-401G>A	upstream_gene_variant		NP_001291646.4	P60484
PTEN	NM_001304718.2 link	c.-1626G>A	upstream_gene_variant		NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
PTEN	ENST00000371953.8 link	c.-921G>A	upstream_gene_variant	1	NM_000314.8	ENSP00000361021.3	P60484-1
KLLN	ENST00000445946.5 link	c.-1062C>T	upstream_gene_variant	6	NM_001126049.2	ENSP00000392204.2	B2CW77
ENSG00000289051	ENST00000692337.1 link	c.-10G>A	upstream_gene_variant			ENSP00000509326.1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000849

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000958

GnomAD4 exome

AF:

0.0000811

AC:

AN:

234200

Hom.:

Cov.:

AF XY:

0.0000924

AC XY:

AN XY:

119058

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.000436

Gnomad4 NFE exome

AF:

0.0000467

Gnomad4 OTH exome

AF:

0.0000650

GnomAD4 genome

AF:

0.000105

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000849

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000958

Bravo

AF:

0.0000491

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PTEN: BP4 -

Oct 05, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Describes a nucleotide substitution 921 basepairs upstream of the ATG translational start site in the PTEN promoter region; Observed in at least one individual with breast cancer (Guindalini et al., 2022); A different variant at the same position, published as c.-920G>T, was observed in a patient with features of Cowden syndrome and was reported to alter a putative Sp1 transcription factor binding site (Zhou et al., 2003); Also known as c.-920G>A; This variant is associated with the following publications: (PMID: 27720647, 12844284, 35264596) -

PTEN hamartoma tumor syndrome

Uncertain:1

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Nov 25, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PTEN c.-921G>A (also known as c.-920G>A in RefSeq) is located in the untranscribed region upstream of the of the PTEN gene. The variant allele was found at a frequency of 9.9e-05 in 150812 control chromosomes, predominantly at a frequency of 0.00085 within the Finnish subpopulation in the gnomAD database (v3.1, genomes dataset). The observed variant frequency within the Finnish European control individuals in the gnomAD database is approximately 136-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 a benign polymorphism. The variant, c.-921G>A, has been reported in the literature in at least one individual who participated in a multigene hereditary-cancer testing, however no clinical information was provided (Mu_2016). 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. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=2), or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome

Benign:1

Dec 07, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

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