10-87965364-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP7BS1

This summary comes from the ClinGen Evidence Repository: PTEN c.1104T>C (p.D368=) 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 0.0057 (0.57%, 130/22,966 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533)BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact.BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000293/MONDO:0017623/003

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

PTEN
NM_000314.8 synonymous

Scores

2

Clinical Significance

Likely benign reviewed by expert panel B:15

Conservation

PhyloP100: 0.600
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
For more information check the summary or visit ClinGen Evidence Repository.
BP7
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
PTENNM_000314.8 linkuse as main transcriptc.1104T>C p.Asp368= synonymous_variant 9/9 ENST00000371953.8 NP_000305.3
PTENNM_001304717.5 linkuse as main transcriptc.1623T>C p.Asp541= synonymous_variant 10/10 NP_001291646.4
PTENNM_001304718.2 linkuse as main transcriptc.513T>C p.Asp171= synonymous_variant 9/9 NP_001291647.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PTENENST00000371953.8 linkuse as main transcriptc.1104T>C p.Asp368= synonymous_variant 9/91 NM_000314.8 ENSP00000361021 P1P60484-1

Frequencies

GnomAD3 genomes
AF:
0.00148
AC:
225
AN:
152156
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00500
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000851
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000476
AC:
114
AN:
239404
Hom.:
0
AF XY:
0.000409
AC XY:
53
AN XY:
129458
show subpopulations
Gnomad AFR exome
AF:
0.00618
Gnomad AMR exome
AF:
0.000386
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000168
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000188
Gnomad OTH exome
AF:
0.000170
GnomAD4 exome
AF:
0.000181
AC:
263
AN:
1456954
Hom.:
1
Cov.:
33
AF XY:
0.000166
AC XY:
120
AN XY:
724524
show subpopulations
Gnomad4 AFR exome
AF:
0.00584
Gnomad4 AMR exome
AF:
0.000384
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000933
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.000399
GnomAD4 genome
AF:
0.00148
AC:
226
AN:
152274
Hom.:
1
Cov.:
32
AF XY:
0.00146
AC XY:
109
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.00501
Gnomad4 AMR
AF:
0.000850
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000447
Hom.:
0
Bravo
AF:
0.00174

ClinVar

Significance: Likely benign
Submissions summary: Benign:15
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 17, 2013- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 09, 2019Variant summary: PTEN c.1104T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00057 in 265518 control chromosomes, predominantly at a frequency of 0.0057 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 912 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 a benign polymorphism found primarily in populations of African origin. The variant was also detected in the FLOSSIES database in 26 African American women who are cancer free and older than age 70, providing further supporting evidence for a benign role. However, these observations need to be cautiously considered due to the potential of the PTEN pseudogene being captured at this site. c.1104T>C has been reported in the literature in one Cowden Syndrome study but it was unclear if found in patients or controls (Nizialek_2015) and in one individual with prostate cancer (Dong_1998). These reports do not provide unequivocal conclusions about association of the variant with Cowden Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as likely benign (4x) and once as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitterclinical testingGeneDxJun 30, 2014This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
PTEN hamartoma tumor syndrome Benign:3
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Likely benign, reviewed by expert panelcurationClingen PTEN Variant Curation Expert Panel, ClingenSep 14, 2016PTEN c.1104T>C (p.D368=) 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 0.0057 (0.57%, 130/22,966 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533) BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact. BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted. -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submittercurationSema4, Sema4Dec 03, 2020- -
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthOct 19, 2022- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 23, 2014This 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. -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesDec 16, 2021- -
Benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoOct 04, 2022- -
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioSep 21, 2021- -
Cowden syndrome 1 Benign:1
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The PTEN p.Asp368= variant was identified in 2 of 2104 proband chromosomes (frequency: 0.001) from individuals or families with prostate cancer or Cowden syndrome (Nizialek 2015, Dong 1998). The variant was also identified in dbSNP (ID: rs35979531) as "With Uncertain significance, other allele", ClinVar (classified as benign by GeneDx, Invitae and two other submitters; and as likely benign by Ambry Genetics, Color Genomics and one other submitter), and LOVD 3.0 (2x). The variant was not identified in the Cosmic or Zhejiang University databases. The variant was identified in 151 of 265518 chromosomes at a frequency of 0.0006, 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 130 of 22966 chromosomes (freq: 0.006), Other in 2 of 6210 chromosomes (freq: 0.0003), Latino in 12 of 33662 chromosomes (freq: 0.0004), European in 2 of 119394 chromosomes (freq: 0.00002), and South Asian in 5 of 29884 chromosomes (freq: 0.0002); it was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Asp368= 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.58
CADD
Benign
7.3
DANN
Benign
0.54

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.

Other links and lift over

dbSNP: rs35979531; hg19: chr10-89725121; API