Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000221956 | SCV000276872 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2015-06-28 | criteria provided, single submitter | clinical testing | Lines of evidence used in support of classification: Well-characterized mutation at same position,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species |
| Gene |
RCV000489810 | SCV000577525 | pathogenic | not provided | 2017-03-24 | criteria provided, single submitter | clinical testing | The G132V variant in the PTEN gene has previously been published in individuals suspicious for PTEN-hamartoma tumor syndrome, and was de novo in at least one individual (Sarquis et al., 2006; Tekin et al., 2006; Pilarski et al., 2011). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G132V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same residue (G132D, G132A) have been reported in association with PTEN-hamartroma tumor syndrome supporting the functional importance of this region of the protein (Derrey et al., 2004; Tan et al., 2007). Based on the currently available evidence, we consider G132V to be pathogenic. |
| Invitae | RCV000008302 | SCV000766782 | likely pathogenic | PTEN hamartoma tumor syndrome | 2018-12-13 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with valine at codon 132 of the PTEN protein (p.Gly132Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with pediatric PTEN hamartoma tumor syndrome with unusual phenotypic manifestations (PMID: 16752378). In addition, this variant has been reported in individuals with Cowden syndrome (PMID: 16773562, Invitae), and individuals referred for PTEN testing who are highly suspicious of having PTEN hamartoma tumor syndrome (PMID: 21659347). ClinVar contains an entry for this variant (Variation ID: 7852). 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. 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. |
| OMIM | RCV000656691 | SCV000028509 | pathogenic | Cowden syndrome 1 | 2006-07-01 | no assertion criteria provided | literature only |