ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.395G>A (p.Gly132Asp) (rs121909241)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000544638 SCV000863470 likely pathogenic PTEN hamartoma tumor syndrome 2018-04-06 reviewed by expert panel curation PTEN c.395G>A (p.G132D) meets criteria to be classified as likely pathogenic 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). PM2: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000279163.8) PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 25288137, PMID 23335809, PMID 23470840, internal laboratory contributor(s)) 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078616 SCV000110472 uncertain significance not provided 2017-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000078616 SCV000279163 likely pathogenic not provided 2018-06-29 criteria provided, single submitter clinical testing This variant is denoted PTEN c.395G>A at the cDNA level, p.Gly132Asp (G132D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). This variant has been reported in several individuals with clinical histories consistent with PTEN hamartoma tumor syndrome (PHTS), including at least two individuals with pathognomonic features of Cowden syndrome (Derrey 2004, Heindl 2012, Busch 2013, Bubien 2013, Frazier 2015). PTEN Gly132Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PTEN Gly132Asp occurs at a position that is conserved across species and is located within the phosphatase tensin-type domain (Nguyen 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. The currently available information regarding this variant suggests pathogenicity; however functional data examining the effect of this variant on the function of the protein has not been published. We therefore consider PTEN Gly132Asp to be a likely pathogenic variant.
Invitae RCV000544638 SCV000645579 likely pathogenic PTEN hamartoma tumor syndrome 2018-09-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 132 of the PTEN protein (p.Gly132Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with PTEN hamartoma tumor syndrome (PMID: 23470840, 22266152, 20600018, 27477328). ClinVar contains an entry for this variant (Variation ID: 92822). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Gly132 amino acid residue in PTEN. Other variant that disrupt this residue have been observed in affected individuals (PMID: 16752378, 16773562,21659347), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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