rs11202592

Positions:

• chr10-87864461-C-G
• chr10-87864461-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: PTEN c.-9C>G (NC_000010.10:g.89624218C>G) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Allele frequency of 0.048 (4.8%, 903/18,870 alleles) in the East Asian subpopulation of the gnomAD cohort. (PMID 27535533) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000663/MONDO:0017623/003

• Frequency:
  • Genomes: 𝑓 0.0020 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (43 hom.)
• Consequence: PTEN NM_000314.8 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:18
• Conservation: PhyloP100: 2.55

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.-9C>G		5_prime_UTR_variant	1/9	ENST00000371953.8
PTEN	NM_001304717.5	c.511C>G	p.Leu171Val	missense_variant	2/10
PTEN	NM_001304718.2	c.-714C>G		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.-9C>G		5_prime_UTR_variant	1/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 311 AN: 152220 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0529

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00382 AC: 961 AN: 251482 Hom.: 20 AF XY: 0.00349 AC XY: 475 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0473

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00148 AC: 2164 AN: 1461106 Hom.: 43 Cov.: 30 AF XY: 0.00145 AC XY: 1057 AN XY: 726880

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0419

Gnomad4 SAS exome AF: 0.00241

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.00262

GnomAD4 genome AF: 0.00205 AC: 312 AN: 152338 Hom.: 10 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74496

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0533

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.00251

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 21, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2018	- -

Cowden syndrome 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 08, 2023	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

PTEN hamartoma tumor syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Nov 09, 2016	PTEN c.-9C>G (NC_000010.10:g.89624218C>G) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). BA1: Allele frequency of 0.048 (4.8%, 903/18,870 alleles) in the East Asian subpopulation of the gnomAD cohort. (PMID 27535533) -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 23796801, 14623110, 23315997) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 06, 2015	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 14, 2021

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PTEN c.-9C>G variant was identified in 137 of 2170 proband chromosomes (frequency: 0.06) from individuals or families with Li-Fraumeni syndrome, ESCC, GCA, breast, thyroid cancer (Ge 2008, Ng 2014, Yang 2013). The variant was also identified in the following databases: dbSNP (ID: rs11202592) as With other allele, ClinVar (classified as benign by Ambry Genetics, Invitae, PreventionGenetics, Counsyl, Color Genomics; classified as likely benign by Illumina), Clinvitae (classified as benign by ClinVar), and the Zhejiang Colon Cancer Database. The variant was not identified in the LOVD 3.0 database. The variant was identified in control databases in 1000 (24 homozygous) of 277238 chromosomes at a frequency of 0.0036 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The case study by Akouchekian (2015) suggests the substitution of C to G in the 5′UTR results in a recovery of the periodical occurrence of the G residue (gtcccagacATGa), which closely matches the consensus sequence that helps ribosomes stay in-frame during translation, and it may affect the expression of the PTEN gene. The population-based case-control study by Ge (2008) identify the overall PTEN –9C/G genotype distributions in ESCC, GCA patients were not significantly different from that in healthy controls (χ2 = 0.19 and 0.42; P = 0.66 and 0.52, respectively). In addition, in vitro cell transfection showed that the variant (–9G) allele resulted in a significantly higher level of protein expression compared with the wild-type allele (–9C) (Ishihara 2003). In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs11202592; hg19: chr10-89624218; COSMIC: COSV64295334; COSMIC: COSV64295334;