ClinVar Miner

Submissions for variant NM_000314.4(PTEN):c.406T>C (p.Cys136Arg) (rs786201044)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162428 SCV000212775 pathogenic Hereditary cancer-predisposing syndrome 2017-09-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification
GeneDx RCV000212881 SCV000222112 pathogenic not provided 2019-01-07 criteria provided, single submitter clinical testing This pathogenic variant is denoted PTEN c.406T>C at the cDNA level, p.Cys136Arg (C136R) at the protein level, and results in the change of a Cysteine to an Arginine (TGT>CGT). This variant has been observed in association with PTEN hamartoma tumor syndrome (Paparo 2013, Bubien 2013, He 2013). Functional studies demonstrated that PTEN Cys136Arg results in reduced PTEN protein levels and increased cytosolic proteasome activity (He 2013). PTEN Cys136Arg was not observed in large population cohorts (Lek 2016). PTEN Cys136Arg is located in the phosphatase domain as well as the ATP binding motif (Lobo 2009, Molinari 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785388 SCV000923959 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Integrated Genetics/Laboratory Corporation of America RCV000587477 SCV000696534 pathogenic Cowden syndrome 2017-08-21 criteria provided, single submitter clinical testing Variant summary: The PTEN c.406T>C (p.Cys136Arg) variant located in the Protein-tyrosine phosphatase-like domain involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 121500 control chromosomes. Multiple publications have cited the variant in affected indivdiuals diagnosed with Cowden Syndrome, BRRS, and PHTS, which was found to cosegregate with disease in multiple families. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Functional studies have demonstrated an impact of this variant on protein stability leading to increased proteasome activity which has been reported as a hallmark of human cancers. Taken together, this variant is classified as pathogenic.
Invitae RCV000463307 SCV000541633 pathogenic PTEN hamartoma tumor syndrome 2018-05-17 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 136 of the PTEN protein (p.Cys136Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency) . This variant has been reported in individuals with Cowden syndrome (PMID: 10848731, 20600018, 24778394), PTEN hamartoma tumor syndrome (PMID: 21343951, 22520842, 23335809), and Bannayan-Riley-Ruvalcaba syndrome (PMID: 23886400, 21659347).  ClinVar contains an entry for this variant (Variation ID: 183726). Experimental studies have shown that this variant affects the stability of the PTEN protein (PMID: 23475934). For these reasons, this variant has been classified as Pathogenic.
McDonnell Genome Institute,Washington University in St. Louis RCV000202582 SCV000257334 pathogenic Acute megakaryoblastic leukemia; Mediastinal germ cell tumor 2015-10-22 no assertion criteria provided research

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