chr10-87931071-G-A
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. BS2_SupportingBS1PP2
This summary comes from the ClinGen Evidence Repository: PTEN c.235G>A (p.A79T) 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 0.0045 (0.45%, 9/1984 alleles) in the GME variome. (PMID 27428751)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) SCV000222198.12)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000358/MONDO:0017623/003
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
PTEN
NM_000314.8 missense
NM_000314.8 missense
Scores
2
5
12
Clinical Significance
Conservation
PhyloP100: 4.29
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 -4 ACMG points.
PP2
For more information check the summary or visit ClinGen Evidence Repository.
BS1
For more information check the summary or visit ClinGen Evidence Repository.
BS2
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PTEN | NM_000314.8 | c.235G>A | p.Ala79Thr | missense_variant | 4/9 | ENST00000371953.8 | NP_000305.3 | |
| PTEN | NM_001304717.5 | c.754G>A | p.Ala252Thr | missense_variant | 5/10 | NP_001291646.4 | ||
| PTEN | NM_001304718.2 | c.-516G>A | 5_prime_UTR_variant | 3/9 | NP_001291647.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PTEN | ENST00000371953.8 | c.235G>A | p.Ala79Thr | missense_variant | 4/9 | 1 | NM_000314.8 | ENSP00000361021.3 |
Frequencies
GnomAD3 genomes 0.0000793 AC: 12AN: 151248Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000108 AC: 27AN: 250170Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135264
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ClinVar
Significance: Likely benign
Submissions summary: Pathogenic:1Uncertain:7Benign:15
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:4
| Uncertain significance, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | PTEN: PP2, PP3, BS1 - |
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 25, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 04, 2020 | This variant is associated with the following publications: (PMID: 22703879, 26800850, 25980754, 25669429, 30728895, 12789288, 25527629, 10923032, 21659347, 21956414, 16171945, 23161105, 12372056, 21343951, 27720647, 27600092, 11297763, 24142049, 9619835, 21194675, 27477328, 28007035, 25925381, 22076652, 28873162, 29641532, 29371908, 29785012, 29706350, 31159747, 31209962, 31144778, 32350270, 32366478) - |
PTEN hamartoma tumor syndrome Uncertain:1Benign:3
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Jul 10, 2015 | - - |
| Likely benign, reviewed by expert panel | curation | Clingen PTEN Variant Curation Expert Panel, Clingen | Apr 06, 2018 | PTEN c.235G>A (p.A79T) 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 0.0045 (0.45%, 9/1984 alleles) in the GME variome. (PMID 27428751) 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) SCV000222198.12) PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. - |
| Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 11, 2019 | 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 | Oct 09, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 15, 2022 | - - |
Cowden syndrome 1 Pathogenic:1Uncertain:1Benign:1
| Pathogenic, no assertion criteria provided | clinical testing | AlTemaimi Lab, Faculty of Medicine, Kuwait University | May 19, 2017 | CMT panel and gene duplication assays were negative and investigative exome sequencing was conducted. Clinical presentation is 80% match with Cowden Syndrome (exception unilateral pes cavus). - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 17, 2015 | - - |
| 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. - |
Breast and/or ovarian cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 26, 2022 | - - |
Intellectual disability Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Apr 20, 2020 | - - |
Macrocephaly-autism syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Carcinoma of colon Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PTEN p.Ala79Thr variant was identified in 10 of 47,988 proband chromosomes (frequency: 0.0002) from individuals or families with Bannayan-Riley Ruvalcaba syndrome, Cowden syndrome, PTEN hamartoma tumour syndrome, Lynch Syndrome, or ovarian or breast cancer and was present in 2 of 23,624 control chromosomes (frequency: 0.00008) from healthy individuals (Momozawa 2018, Figer 2002, Pilarski 2011, Tan 2011, Mester 2011, Dominguez-Valentin 2018, Nizialek 2015, Yurgelun 2015, Ngeow 2011). The variant was identified in dbSNP (rs202004587) as “with uncertain significance allele”, ClinVar (classified as likely benign by ClinGen PTEN Expert Panel in 2018, Ambry Genetics, GeneDx, and Color; as uncertain significance by Invitae, PreventionGenetics, Counsyl and 7 other submitters; and as pathogenic by Kuwait University) and LOVD 3.0 (observed 6x). The variant was identified in control databases in 29 of 281,404 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 22 of 128,158 chromosomes (freq: 0.0002), South Asian in 5 of 30,560 chromosomes (freq: 0.0002), and Other in 1 of 7170 chromosomes (freq: 0.00004), while it was not observed in the African, Latino, Ashkenazi Jewish, East Asian or Finnish populations. However, this variant was also identified at an allele frequency of 0.005 in a Middle Eastern population, increasing the likelihood this could be a low frequency benign variant (Scott 2016). This variant has been identified in the homozygous state in one unaffected individual, decreasing the likelihood that this variant has clinical significance (PTEN expert panel internal data, per ClinVar entry dated April 6, 2018). The p.Ala79 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 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. - |
PTEN-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 24, 2019 | 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). - |
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 | Apr 27, 2022 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at