ClinVar Miner

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

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Total submissions: 6
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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 pathogenic not provided 2021-09-11 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: loss of phosphatase activity (Mighell et al., 2018); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19457929, 24475377, 29706350, 33509259, 27535533, 32037394, 27514801, 27477328, 20600018, 15120218, 22266152, 23335809, 25288137, 23470840, 26919320)
Invitae RCV000544638 SCV000645579 pathogenic PTEN hamartoma tumor syndrome 2020-08-03 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 several individuals affected with PTEN hamartoma tumor syndrome (PMID: 23470840, 22266152, 23335809, 20600018, 27477328). ClinVar contains an entry for this variant (Variation ID: 92822). This variant has been reported to affect PTEN protein function (PMID: 29706350). This variant disrupts the p.Gly132 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been observed in individuals with PTEN-related conditions (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. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001021527 SCV001183154 likely pathogenic Hereditary cancer-predisposing syndrome 2019-02-26 criteria provided, single submitter clinical testing The p.G132D variant (also known as c.395G>A), located in coding exon 5 of the PTEN gene, results from a G to A substitution at nucleotide position 395. The glycine at codon 132 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in several individuals that either met clinical criteria for PTEN hamartoma tumor syndrome (PHTS) or had features consistent with PHTS (Busch RM et al. Genet. Med., 2013 Jul;15:548-53; Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; Heindl M et al. Gastroenterology, 2012 May;142:1093-1096.e6; Frazier TW et al. Mol. Psychiatry, 2015 Sep;20:1132-8; Chen HH et al. J. Allergy Clin. Immunol., 2017 Feb;139:607-620.e15). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000544638 SCV001467945 likely pathogenic PTEN hamartoma tumor syndrome 2020-12-11 criteria provided, single submitter clinical testing Variant summary: PTEN c.395G>A (p.Gly132Asp) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain (IPR003595) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251384 control chromosomes (gnomAD). c.395G>A has been reported in the literature in individuals affected with PTEN Hamartoma Tumor Syndrome as well as Cowden syndrome (example: Bubien_2014, Busch_2013, Chen_2017, Derrey_2004, Heald_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cite the variant as likely pathogenic/pathogenic or uncertain significance. An expert panel (ClinGen PTEN Variant Curation Expert Panel) also cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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