10-87961014-C-T
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_000314.8(PTEN):c.922C>T(p.Arg308Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,594 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
PTEN
NM_000314.8 missense
NM_000314.8 missense
Scores
10
9
Clinical Significance
Conservation
PhyloP100: 2.11
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTEN. . Gene score misZ: 3.4883 (greater than the threshold 3.09). Trascript score misZ: 4.1129 (greater than threshold 3.09). The gene has 209 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. GenCC has associacion of the gene with Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, macrocephaly-autism syndrome, Cowden syndrome 1, Cowden disease, Proteus-like syndrome, leiomyosarcoma, activated PI3K-delta syndrome, PTEN hamartoma tumor syndrome, glioma susceptibility 2, renal cell carcinoma.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PTEN | NM_000314.8 | c.922C>T | p.Arg308Cys | missense_variant | 8/9 | ENST00000371953.8 | NP_000305.3 | |
| PTEN | NM_001304717.5 | c.1441C>T | p.Arg481Cys | missense_variant | 9/10 | NP_001291646.4 | ||
| PTEN | NM_001304718.2 | c.331C>T | p.Arg111Cys | missense_variant | 8/9 | NP_001291647.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461594Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2AN XY: 727112
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1461594
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36
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2
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727112
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GnomAD4 genome
GnomAD4 genome
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31
Bravo
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 02, 2023 | It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an affected individual with breast cancer in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PTEN)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2016 | This variant is denoted PTEN c.922C>T at the cDNA level, p.Arg308Cys (R308C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in melanoma and glioblastoma tumors (Fiano 2004, Abdel-Rahman 2006). PTEN Arg308Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PTEN Arg308Cys occurs at a position that is conserved in mammals and is located in the C2 domain (Wang 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PTEN Arg308Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | PTEN: PM2, PP2 - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 01, 2022 | This missense variant replaces arginine with cysteine at codon 308 of the PTEN protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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 GRCh38:10:87961014:C>T was assigned evidence codes ['BS3_Supporting', 'BP4'] and an overall classification of Likely benign - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 29, 2024 | The p.R308C variant (also known as c.922C>T), located in coding exon 8 of the PTEN gene, results from a C to T substitution at nucleotide position 922. The arginine at codon 308 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant demonstrated "wild-type-like" intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was reported as "wild-type-like" (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
PTEN hamartoma tumor syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 23, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 308 of the PTEN protein (p.Arg308Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 420367). 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%. 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | - - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
PTEN-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 11, 2024 | The PTEN c.922C>T variant is predicted to result in the amino acid substitution p.Arg308Cys. This variant has been reported in the literature in one individual with breast cancer (Breast Cancer Association Consortium et al 2021. PubMed ID: 33471991). Functional studies showed no significant effect of this variant on lipid phosphatase activity or on the abundance of intracellular protein (Matreyek KA et al 2018. PubMed ID: 29785012; Mighell TL et al 2018. PubMed ID: 29706350). This variant is absent in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is classified as a variant of uncertain significance by multiple submitters in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/420367/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Malignant tumor of prostate;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 22, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.
REVEL
Uncertain
Sift
Benign
T;.
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MutPred
Gain of helix (P = 0.062);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at