ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.403A>G (p.Ile135Val) (rs587782360)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131316 SCV000186289 pathogenic Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Other strong data supporting pathogenic classification,Well-characterized mutation at same position,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx RCV000521053 SCV000617323 likely pathogenic not provided 2017-10-09 criteria provided, single submitter clinical testing This variant is denoted PTEN c.403A>G at the cDNA level, p.Ile135Val (I135V) at the protein level, andresults in the change of an Isoleucine to a Valine (ATA>GTA). This variant has been reported in individuals with familialBannayan–Riley–Ruvalcaba (BRR) and Classical Cowden syndrome according to International Consortium criteria(Marsh 1999, Caux 2007, Bubien 2013). Caux et al. (2007) reported PTEN Ile135Val to segregate in seven affectedfamily members with Cowden syndrome and to be absent in four unaffected relatives. PTEN Ile135Val was notobserved in large population cohorts (Lek 2016). Since Isoleucine and Valine share similar properties, this isconsidered a conservative amino acid substitution. PTEN Ile135Val occurs at a position that is conserved acrossspecies and is located in ATP binding motifs of the Phosphatase domain (Lobo 2009, Molinari 2014). In silico analysesare inconsistent regarding the effect this variant may have on protein structure and function. Based on the currentlyavailable evidence, we consider PTEN Ile135Val to be a likely pathogenic variant
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785581 SCV000924155 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000645036 SCV000766775 pathogenic PTEN hamartoma tumor syndrome 2017-10-06 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 135 of the PTEN protein (p.Ile135Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with PTEN hamartoma tumor syndrome (PMID: 23335809), and an individual with Bannayan-Riley-Ruvalcaba syndrome (PMID: 10400993). It was also shown to segregate with Cowden syndrome in a single family (PMID: 17392703). ClinVar contains an entry for this variant (Variation ID: 142287). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Ile135Arg) has been determined to be pathogenic (PMID: 16894538). This suggests that the isoleucine residue is critical for PTEN protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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