10-87863327-C-T

Position:

chr10-87863327-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP2BS1

This summary comes from the ClinGen Evidence Repository: PTEN c.-1142C>T (NC_000010.10:g.89623084C>T) meets criteria to be classified as likely benign 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: Allele frequency of 0.0049 (0.49%, 8/1622 alleles) in the East Asian subpopulation of the gnomAD cohort. (PMID 27535533) BP2: Observed in trans with a pathogenic or likely pathogenic PTEN variant, at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants. (Internal laboratory contributors SCV000187279.1, SCV000149465.6) LINK:https://erepo.genome.network/evrepo/ui/classification/CA151480/MONDO:0017623/003

Frequency

Genomes: 𝑓 0.00054 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 2 hom. )

Consequence

KLLN
NM_001126049.2 5_prime_UTR

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:7

Conservation

PhyloP100: 0.830

Variant links:

Genes affected

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:

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 Likely_benign. Variant got -5 ACMG points.

BP2

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLLN	NM_001126049.2 linkuse as main transcript	c.-840G>A		5_prime_UTR_variant	1/1	ENST00000445946.5	NP_001119521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLLN	ENST00000445946.5 linkuse as main transcript	c.-840G>A		5_prime_UTR_variant	1/1		NM_001126049.2	ENSP00000392204	P1
PTEN	ENST00000688308.1 linkuse as main transcript	c.-17+214C>T		intron_variant				ENSP00000508752	P1	P60484-1

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0108

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00143

GnomAD4 exome

AF:

0.00163

AC:

224

AN:

137082

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

103

AN XY:

67914

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0150

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000274

Gnomad4 NFE exome

AF:

0.000241

Gnomad4 OTH exome

AF:

0.00102

GnomAD4 genome

AF:

0.000538

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0108

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000231

Hom.:

Bravo

AF:

0.000540

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2018	This variant is associated with the following publications: (PMID: 20862607, 16424003, 16773562) -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	PTEN: BS1, BS2 -

not specified

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 25, 2024	Variant summary: PTEN c.-1143C>T is located in the untranscribed region upstream of the PTEN gene region. The variant allele was found at a frequency of 0.00038 in 31370 control chromosomes. The observed variant frequency is approximately 61 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTEN causing Cowden Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. c.-1143C>T has been reported in the literature in individuals affected with Cowden Syndrome (e.g. Sarquis_2006, Shiohama_2020). However, these reports do not provide unequivocal conclusions about association of the variant with Cowden Syndrome. Several publications report experimental evidence evaluating an impact on transcriptional activity and interaction with p53, however, do not allow convincing conclusions about the functional effects of the variant (e.g. Tang_2006, Ohsaka_2010). The following publications have been ascertained in the context of this evaluation (PMID: 25669429, 20862607, 16773562, 32162846, 16424003). ClinVar contains an entry for this variant (Variation ID: 127661). Based on the evidence outlined above, the variant was classified as benign. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 10, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2024	- -

PTEN hamartoma tumor syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 10, 2023	- -
Likely benign, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Apr 06, 2018	PTEN c.-1142C>T (NC_000010.10:g.89623084C>T) meets criteria to be classified as likely benign 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: Allele frequency of 0.0049 (0.49%, 8/1622 alleles) in the East Asian subpopulation of the gnomAD cohort. (PMID 27535533) BP2: Observed in trans with a pathogenic or likely pathogenic PTEN variant, at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants. (Internal laboratory contributors SCV000187279.1, SCV000149465.6) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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