10-87894077-C-T

Position:

• chr10-87894077-C-T

Variant summary

Our verdict is Likely benign. Variant got -7 ACMG points: 0P and 7B. BS2_Supporting BS1 BP7 BP5

This summary comes from the ClinGen Evidence Repository: PTEN c.132C>T (p.G44=) meets criteria to be classified as likely 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).BS1: Allele frequency of 0.167 (1.67%, 463/276,792 alleles) in the gnomAD cohort. (PMID 27535533)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. (Internal laboratory contributor(s) SCV000212700.3)BP5: Variant found in multiple cases with alternate molecular basis for disease. (Internal laboratory contributor(s) SCV000212700.3)BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000318/MONDO:0017623/003

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (6 hom.)
• Consequence: PTEN NM_000314.8 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:27
• Conservation: PhyloP100: -0.209

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 Likely_benign. Variant got -7 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.132C>T	p.Gly44=	synonymous_variant	2/9	ENST00000371953.8
PTEN	NM_001304717.5	c.651C>T	p.Gly217=	synonymous_variant	3/10
PTEN	NM_001304718.2	c.-574C>T		5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.132C>T	p.Gly44=	synonymous_variant	2/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 248 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00369

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00152 AC: 381 AN: 251050 Hom.: 2 AF XY: 0.00150 AC XY: 204 AN XY: 135714

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00301

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00137 AC: 1998 AN: 1460064 Hom.: 6 Cov.: 29 AF XY: 0.00146 AC XY: 1060 AN XY: 726440

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00303

Gnomad4 EAS exome AF: 0.000228

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00381

Gnomad4 NFE exome AF: 0.00146

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74390

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00369

Gnomad4 NFE AF: 0.00290

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00249 Hom.: 0

Bravo AF: 0.00108

Asia WGS AF: 0.000289 AC: 1 AN: 3474

EpiCase AF: 0.00235

EpiControl AF: 0.000948

ClinVar

Significance: Likely benign

Submissions summary: Benign:27

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:10

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 15, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 21, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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	Quest Diagnostics Nichols Institute San Juan Capistrano	May 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 25, 2016	- -

not provided Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PTEN: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2016	Variant summary: The c.132C>T variant affects a non-conserved nucleotide, resulting in no amino acid change. One in-silico tool predicts damaging outcome for this variant. 3/5 programs in Alamut predict that this variant may create a novel 5' splicing donnor site. ESE finder predicts that this variant may affect ESE site of SRp55. However, these predictions are not confirmed by experimental studies. This variant is found in 190/121096 control chromosomes (1 homozygote) at a frequency of 0.001569. These alleles are unlikely from the PTEN pseudogene based on the sequence homology analysis and homozygous occurrences. This frequency is about 282 times of maximal expected frequency of a pathogenic allele (0.0000056), suggesting this variant is benign. In addition, multiple clinical laboratories classified this variant as benign/likely benign. Taken together, this variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 23, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 27, 2023	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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 29, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 27, 2015	- -

PTEN hamartoma tumor syndrome Benign:3

Likely benign, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Nov 09, 2016	PTEN c.132C>T (p.G44=) meets criteria to be classified as likely 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). BS1: Allele frequency of 0.167 (1.67%, 463/276,792 alleles) in the gnomAD cohort. (PMID 27535533) 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. (Internal laboratory contributor(s) SCV000212700.3) BP5: Variant found in multiple cases with alternate molecular basis for disease. (Internal laboratory contributor(s) SCV000212700.3) BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 28, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 18, 2023

- -

Cowden syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PTEN p.Gly44= variant was identified in 3 of 2724 proband chromosomes (frequency: 0.001) from individuals or families with prostate, breast cancer or Cowden syndrome and was not identified in 322 control chromosomes from healthy individuals (Bar-Shira 2006, Kurose 2002, Nizialek 2015). The variant was also identified in large population study by Momozawa (2018) in 6 of 14102 female chromosomes (frequency: 0.0004), and 4 in 22482 female control chromosomes (frequency: 0.0002) and 7 in 24980 male control chromosomes (frequency: 0.0003). The variant was also identified in dbSNP (ID: rs150651961) as "With other allele", ClinVar (classified as benign by Invitae, ARUP and four other submitters; as likely benign by eight submitters), LOVD 3.0 (7x as benign or likely benign). The variant was identified in control databases in 463 of 276792 chromosomes (3 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24028 chromosomes (freq: 0.0001), Other in 16 of 6452 chromosomes (freq: 0.003), Latino in 5 of 34378 chromosomes (freq: 0.0002), European in 319 of 126434 chromosomes (freq: 0.003), Ashkenazi Jewish in 33 of 10142 chromosomes (freq: 0.003), East Asian in 3 of 18856 chromosomes (freq: 0.0002), Finnish in 84 of 25724 chromosomes (freq: 0.003); it was not observed in the and South Asian populations. The p.Gly44= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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	-0.36
CADD	Benign	9.0
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.24		Position offset: 32

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs150651961; hg19: chr10-89653834; COSMIC: COSV64295419;