rs587782434

Positions:

• chr10-87931033-ACTTTT-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS3 BS1

This summary comes from the ClinGen Evidence Repository: PTEN c.210-7_210-3delCTTTT (IVS3-7_IVS3-3delCTTTT) meets criteria to be classified as 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 0.00136 (0.14%, 14/10,306 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort. (PMID 27535533) BS3: Intronic OR synonymous variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID 28677221) LINK:https://erepo.genome.network/evrepo/ui/classification/CA059460/MONDO:0017623/003

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (2 hom.)
• Consequence: PTEN NM_000314.8 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign reviewed by expert panel P:1 U:5 B:18
• Conservation: PhyloP100: 3.82

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.210-7_210-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000371953.8
PTEN	NM_001304717.5	c.729-7_729-3del		splice_region_variant, intron_variant
PTEN	NM_001304718.2	c.-540-7_-540-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.210-7_210-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000314.8	P1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 151628 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000296

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000289 AC: 72 AN: 249456 Hom.: 0 AF XY: 0.000230 AC XY: 31 AN XY: 134912

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00140

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000302

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000429 AC: 621 AN: 1446668 Hom.: 2 AF XY: 0.000391 AC XY: 282 AN XY: 720342

Gnomad4 AFR exome AF: 0.0000907

Gnomad4 AMR exome AF: 0.000225

Gnomad4 ASJ exome AF: 0.000927

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000478

Gnomad4 OTH exome AF: 0.000652

GnomAD4 genome AF: 0.000237 AC: 36 AN: 151746 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74168

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000296

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000781 Hom.: 0

Bravo AF: 0.000321

Asia WGS AF: 0.000290 AC: 2 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:5 Benign:18

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:1 Uncertain:1 Benign:3

Pathogenic, no assertion criteria provided	research	King Laboratory, University of Washington	Sep 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Mar 05, 2019	PTEN c.210-7_210-3delCTTTT (IVS3-7_IVS3-3delCTTTT) meets criteria to be classified as 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 0.00136 (0.14%, 14/10,306 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort. (PMID 27535533) BS3: Intronic OR synonymous variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID 28677221) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Uncertain:1 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 15, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 21, 2022	Variant summary: PTEN c.210-7_210-3delCTTTT deletes 5 nucleotides located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. One publication reports experimental evidence that this variant affects mRNA splicing (Huang_2000), however, this effect was not confirmed in three other experimental studies (Brown_2000, Chen_2017, Casadei_2019), suggesting the variant does not significantly impact mRNA splicing. The variant allele was found at a frequency of 0.00029 in 249498 control chromosomes (gnomAD). The observed variant frequency is approximately 18 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTEN causing Hereditary Breast And Ovarian Cancer Syndrome (1.6e-05), strongly suggesting that the variant is benign. c.210-7_210-3delCTTTT has been reported in the literature in individuals affected with different types of cancer without unequivocal conclusion. Fourteen ClinVar submitters, including one expert panel (ClinGen PTEN Variant Curation Expert Panel), have assessed the variant since 2014: one classified the variant as pathogenic, five as VUS, five as likely benign, and three (including the expert panel) as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PTEN: BP4 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2018	This variant is associated with the following publications: (PMID: 21659347, 22995991, 11156385, 16287957, 28677221, 11120338) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PTEN c.210-7_210-3del variant was identified in 18 of 5644 proband chromosomes (frequency: 0.003) from individuals or families with endometrial cancer, Cowden syndrome, Li Fraumeni, and breast cancer (Black 2004, Brown 2000, Chen 2017 , Hobert 2012, Pilarski 2011, Sweet 2005, Tung 2015). The variant was also identified in dbSNP (ID: rs587780544) as “With other allele”, in ClinVar (with conflicting interpretations of pathogenicity; as likely benign by GeneDx, Invitae, and Integrated Genetics, and as uncertain significance by Ambry, Illumina, Counsyl, University of Chicago, Quest Diagnostics, EGL Genetic Diagnostics, and Cleveland Clinic), Cosmic (in endometrioid carcinoma), LOVD 3.0, and in the Zhejiang University Database (in individuals with Familial Juvenile Polyposis). The variant was not identified in the MutDB database. The variant was identified in control databases in 78 of 275204 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: Ashkenazi Jewish in 16 of 10086 chromosomes (freq: 0.002), Other in 4 of 6406 chromosomes (freq: 0.0006), European (Non-Finnish) in 38 of 125410 chromosomes (freq: 0.0003), African in 7 of 23920 chromosomes (freq: 0.0003), Latino in 9 of 34240 chromosomes (freq: 0.0003), East Asian in 3 of 18782 chromosomes (freq: 0.0002), and South Asian in 1 of 30656 chromosomes (freq: 0.00003), while the variant was not observed in the Finnish population. The c.210-7_210-3del variant has inconsistent predictions of pathogenicity in the literature. Two functional studies of patients with Li-Fraumeni and Cowden syndrome showed the variant had no deleterious effect on mRNA processing (Brown 2000, Chen 2017). However, another study found an individual with the variant who met full Cowden syndrome diagnostic criteria exhibited elevated succinate in both plasma and urine, and concluded that the variant may actually be pathogenic (Hobert 2012). Another study of a family in which an unaffected father carried the variant, and his twin daughters both carried the variant and were affected with Juvenile Polyposis, concluded that RT-PCR analysis demonstrated the variant appears to affect RNA splicing (Huang 2000). The c.210-7_210-3del variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 06, 2023	- -

Cowden syndrome 1 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 23, 2015	- -
Uncertain significance, no assertion criteria provided	research	Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute	May 26, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	This variant is considered likely benign. 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. -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 20, 2018	This alteration is classified as likely 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, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 13, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 29, 2020	- -

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

Mar 10, 2023

- -

PTEN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 04, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Nov 11, 2020

The PTEN c.210-7_210-3del5 variant is classified as Benign (BS2, BP6_Strong) PTEN c.210-7_210-3del5 is located in intron 3. This variant has been observed in a healthy control population at a frequency which is inconsistent with expectations given the high penetrance of this condition under curation (BS2). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780544; hg19: chr10-89690790;