10-87960984-C-G
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. BS1_SupportingBS3_SupportingBP4PP2
This summary comes from the ClinGen Evidence Repository: NM_000314.8(PTEN):c.892C>G (p.Gln298Glu) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). BS1_Supporting: Filtering allele frequency of 0.00002132 (0.002132%, 4/24900 African/African American alleles) in gnomAD. BS3_Supporting: Massively parallel functional assay interrogating phosphatase activity demonstrating no statistically significant difference from wild type (PMID:29706350). BP4: REVEL score = 0.229. 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.Variant with benign and pathogenic codes. Classification based on application of Bayesian Classification Framework (PMID:29300386): BS1_P (-1 pt1), BS3_P (-1 pt), BP4 (-1 pt), PP2 (+1 pt) = -2 pts total (Likely Benign). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000623/MONDO:0017623/003
Frequency
Genomes: 𝑓 0.000086 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
PTEN
NM_000314.8 missense
NM_000314.8 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: 2.69
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 -2 ACMG points.
PP2
For more information check the summary or visit ClinGen Evidence Repository.
BP4
For more information check the summary or visit ClinGen Evidence Repository.
BS1
For more information check the summary or visit ClinGen Evidence Repository.
BS3
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.892C>G | p.Gln298Glu | missense_variant | 8/9 | ENST00000371953.8 | NP_000305.3 | |
| PTEN | NM_001304717.5 | c.1411C>G | p.Gln471Glu | missense_variant | 9/10 | NP_001291646.4 | ||
| PTEN | NM_001304718.2 | c.301C>G | p.Gln101Glu | missense_variant | 8/9 | NP_001291647.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000862 AC: 13AN: 150804Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251224Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135778
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:16Benign:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Cowden syndrome 1 Uncertain:4
| Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 19, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 05, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | Jan 22, 2020 | This variant has been reported in the literature in an individual with a Lynch syndrome-associated cancer and/or polyps who also had a pathogenic variant in the MLH1 gene (Yurgelun 2015). This variant has an overall allele frequency of 0.00002 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant may not not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4 - |
not specified Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 24, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 03, 2022 | Variant summary: PTEN c.892C>G (p.Gln298Glu) results in a conservative amino acid change located in the Tensin phosphatase, C2 domain (IPR014020) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251224 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.892C>G has been reported in the literature in an individual affected with Lynch Syndrome (example: Yurgelun_2015). However, this individual also had a co-occurrence with other pathogenic variant (MLH1 c.454-?_1409+?dup/dup exons 6-12), providing supporting evidence for a benign role. Experimental studies have shown that this variant does not alter protein function (examples: Mighell_2018 and Post_2020). Ten submitters (including an expert panel) have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 06, 2017 | The p.Gln298Glu variant in PTEN has been reported in 1 individual with a Lynch s yndrome-associated cancer and/or colon polyps (Yurgelun 2015). This variant has also been reported in ClinVar (associated phenotypes include PTEN hamartoma synd rome and hereditary cancer predisposition syndrome syndrome, Variation ID# 12769 5). This variant has been identified in 2/10354 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs371387815 ).Computational prediction tools suggest that the p.Gln298Glu variant may not im pact the protein, though this information is not predictive enough to rule out p athogenicity. In summary, the clinical significance of the p.Gln298Glu variant i s uncertain. - |
PTEN hamartoma tumor syndrome Uncertain:2Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 298 of the PTEN protein (p.Gln298Glu). This variant is present in population databases (rs371387815, gnomAD 0.02%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127695). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt PTEN function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect PTEN function (PMID: 32350270). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
| Likely benign, reviewed by expert panel | curation | Clingen PTEN Variant Curation Expert Panel, Clingen | Aug 04, 2023 | NM_000314.8(PTEN):c.892C>G (p.Gln298Glu) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). BS1_Supporting: Filtering allele frequency of 0.00002132 (0.002132%, 4/24900 African/African American alleles) in gnomAD. BS3_Supporting: Massively parallel functional assay interrogating phosphatase activity demonstrating no statistically significant difference from wild type (PMID: 29706350). BP4: REVEL score = 0.229. 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. Variant with benign and pathogenic codes. Classification based on application of Bayesian Classification Framework (PMID: 29300386): BS1_P (-1 pt1), BS3_P (-1 pt), BP4 (-1 pt), PP2 (+1 pt) = -2 pts total (Likely Benign). - |
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 20, 2024 | This missense variant replaces glutamine with glutamic acid at codon 298 of the PTEN protein. Functional studies have shown that the variant proteins displays phenotypes similar to the wild-type protein in yeast, drosophila, and mammalian cell-based assays (PMID: 29706350, 32350270). This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754), in an individual affected with ovarian cancer (PMID: 32885271), but also in a control cohort (PMID: 24055113). This variant has also been identified in 5/282198 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 26, 2024 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 07, 2022 | This missense variant replaces glutamine with glutamic acid at codon 298 of the PTEN protein. Functional studies have shown that the variant proteins displays phenotypes similar to the wild-type protein in yeast, drosophila, and mammalian cell-based assays (PMID: 29706350, 32350270). This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754), but also in a control cohort (PMID: 24055113). This variant has also been identified in 5/282198 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
| Likely benign, criteria provided, single submitter | curation | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Apr 12, 2024 | Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).For PTEN, two assays measuring activity and abundance were used. If the abundance was categorized as "wt-like" or "possibly wt-like," BS3_Supporting evidence was used. Furthermore, if the cumulative score was greater than -5, BS3_moderate evidence was used. This variant GRCh38:10:87960984:C>G was assigned evidence codes ['BS3_Supporting', 'BP4', 'BS1'] and an overall classification of Likely benign - |
PTEN-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 20, 2024 | The PTEN c.892C>G variant is predicted to result in the amino acid substitution p.Gln298Glu. This variant has been previously reported in at least one individual with suspected Lynch syndrome, who also had a large duplication in the MLH1 gene (Yurgelun et al. 2015. PubMed ID: 25980754). A mutation saturation study assessing in silico and functional data suggests this variant does not significantly impact protein function (Mighell et al. 2018. PubMed ID: 29706350, Table S2). It is reported in 5 of ~282,000 alleles in gnomAD. It is interpreted as likely benign by the ClinGen PTEN Variant Curation Expert Panel in ClinVar and as uncertain significance by other laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/127695/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with a Lynch syndrome-associated cancer and/or polyps who also harbored a pathogenic MLH1 variant (Yurgelun et al., 2015); Published functional studies demonstrate no damaging effect: protein stability and phosphatase activity generally comparable to wild-type (Mighell et al., 2018; Post et al., 2020); This variant is associated with the following publications: (PMID: 25695693, 24055113, 26800850, 27150160, 31006514, 18626510, 32350270, 25980754, 29706350) - |
Bannayan-Riley-Ruvalcaba syndrome;C0376358:Malignant tumor of prostate;C0476089:Endometrial carcinoma;C1168401:Squamous cell carcinoma of the head and neck;C1835047:Melanoma, cutaneous malignant, susceptibility to, 1;C1848599:VACTERL with hydrocephalus;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;C4225426:Thyroid cancer, nonmedullary, 2;CN072330:Cowden syndrome 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
Familial ovarian cancer Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PTEN p.Gln298Glu variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with HNPCC and was present in 1 of 2000 control chromosomes (frequency: 0.0005) from individuals participating in an exome sequencing study of incidental findings (Yurgelun 2015, Dorschner 2013). The variant co-occurred with an MLH1 variant (duplication of exons 6-12) in 1 affected patient (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs371387815) “With Pathogenic, Uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Counsyl, Fulgent Genetics, LMM, GeneDx, Ambry Genetics and CSER_NCGL University of Washington Medical Center). It was not identified in Cosmic, MutDB, LOVD 3.0 or the Zhejiang University Database. The variant was identified in control databases in 5 of 276588 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 4 of 23980 chromosomes (freq: 0.0002) and European Non-Finnish in 1 of 126380 chromosomes (freq: 0.000008), while it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Gln298 residue is conserved in mammals but not in more distantly related organisms. However, 4 of 5 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. This variant is classified as a variant of uncertain significance. - |
Familial cancer of breast Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Aug 11, 2020 | - - |
Glioma susceptibility 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 11, 2023 | - - |
Computational scores
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Name
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AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.
REVEL
Benign
Sift
Benign
T;.
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
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RBP_binding_hub_radar
RBP_regulation_power_radar
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gMVP
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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