chr10-87863385-C-T

Position:

chr10-87863385-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP2BS2_SupportingBS1

This summary comes from the ClinGen Evidence Repository: PTEN c.-1084C>T (NC_000010.10:g.89623142C>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 0.0025 (0.25%, 38/14,966 alleles) in the European subpopulation of the gnomAD cohort. (PMID 27535533)BP2: At least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants. (internal laboratory contributor(s) SCV000149464.4)BS2_P: Meets criteria for BS2 (observed in the homozygous state in at least one healthy or PHTS-unaffected individual) but BS1 is also applied. (PMID 27884173, internal laboratory contributor(s) SCV000149464.4, SCV000185343.1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA151479/MONDO:0017623/003

Frequency

Genomes: 𝑓 0.0033 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 7 hom. )

Consequence

KLLN
NM_001126049.2 5_prime_UTR

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:11

Conservation

PhyloP100: 0.291

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP2

BS1

BS2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLLN	NM_001126049.2 linkuse as main transcript	c.-898G>A		5_prime_UTR_variant	1/1	ENST00000445946.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLLN	ENST00000445946.5 linkuse as main transcript	c.-898G>A		5_prime_UTR_variant	1/1		NM_001126049.2	P1
PTEN	ENST00000688308.1 linkuse as main transcript	c.-17+272C>T		intron_variant				P1	P60484-1

Frequencies

GnomAD3 genomes

AF:

0.00335

AC:

509

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.00483

Gnomad SAS

AF:

0.0197

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00310

Gnomad OTH

AF:

0.00478

GnomAD4 exome

AF:

0.00446

AC:

884

AN:

198008

Hom.:

Cov.:

AF XY:

0.00475

AC XY:

476

AN XY:

100182

show subpopulations

Gnomad4 AFR exome

AF:

0.00141

Gnomad4 AMR exome

AF:

0.00275

Gnomad4 ASJ exome

AF:

0.0217

Gnomad4 EAS exome

AF:

0.000596

Gnomad4 SAS exome

AF:

0.0219

Gnomad4 FIN exome

AF:

0.00194

Gnomad4 NFE exome

AF:

0.00424

Gnomad4 OTH exome

AF:

0.00616

GnomAD4 genome

AF:

0.00334

AC:

509

AN:

152260

Hom.:

Cov.:

AF XY:

0.00330

AC XY:

246

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.0225

Gnomad4 EAS

AF:

0.00484

Gnomad4 SAS

AF:

0.0195

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00310

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.0000542

Hom.:

Bravo

AF:

0.00285

Asia WGS

AF:

0.00982

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Region not covered by ExAC,reported in 1 proband, analysis of patient samples suggests possible impact to PTEN expression, but insufficient evidence for pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2018	- -

PTEN hamartoma tumor syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 17, 2023	- -
Likely benign, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Nov 28, 2018	PTEN c.-1084C>T (NC_000010.10:g.89623142C>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 0.0025 (0.25%, 38/14,966 alleles) in the European subpopulation of the gnomAD cohort. (PMID 27535533) BP2: At least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants. (internal laboratory contributor(s) SCV000149464.4) BS2_P: Meets criteria for BS2 (observed in the homozygous state in at least one healthy or PHTS-unaffected individual) but BS1 is also applied. (PMID 27884173, internal laboratory contributor(s) SCV000149464.4, SCV000185343.1) -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2017	This variant is associated with the following publications: (PMID: 25669429, 21417916, 17427195, 16773562, 12844284, 27884173, 27271787, 30528446, 33509259) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	KLLN: BS1, BS2; PTEN: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 09, 2017	Variant summary: The PTEN variant c.-1084C>T (also known as c.-1085C>T) involves the alteration of a non-conserved nucleotide in the 5'UTR region. One in silico tool predicts a benign outcome for this variant. This variant was found in 28/5008 control chromosomes, predominantly observed in South Asians at a frequency of 0.0163599 (16/978). This frequency greatly exceeds the estimated maximal expected allele frequency of a pathogenic PTEN variant (0.0000063), suggesting this is likely a benign polymorphism found primarily in the populations of origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2013

- -

Cowden syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Aug 14, 2017

- -

Malignant tumor of prostate;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 29, 2021

- -

Cowden syndrome 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

9.0

DANN

Benign

0.86

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