ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.517C>T (p.Arg173Cys) (rs121913293)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218276 SCV000273596 likely pathogenic Hereditary cancer-predisposing syndrome 2015-10-29 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,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other strong data supporting pathogenic classification
Baylor Genetics RCV000850588 SCV000992811 pathogenic Macrocephaly/autism syndrome; VACTERL association with hydrocephalus; Cowden syndrome 1 2017-12-31 criteria provided, single submitter clinical testing
ClinGen PTEN Variant Curation Expert Panel RCV000490574 SCV000840496 pathogenic PTEN hamartoma tumor syndrome 2017-10-18 reviewed by expert panel curation PTEN c.517C>T (p.R173C) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). PS2_VS: At least two proven OR one proven plus two assumed de novo observations in a patient with the disease and no family history. (PMID 17526800, PMID 22628360, internal laboratory contributor(s) SCV000222220.10) PS3: Phosphatase activity <50% of wild type. (PMID 10866302) PM2: Absent in large sequenced populations (PMID 27535533). PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 22628360, PMID 17526800, PMID 17526801) PP1: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. (PMID 22628360) 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.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678738 SCV000804910 pathogenic not specified 2012-02-12 no assertion criteria provided clinical testing
Database of Curated Mutations (DoCM) RCV000445192 SCV000505649 likely pathogenic Neoplasm of brain 2015-07-14 no assertion criteria provided literature only
Fulgent Genetics,Fulgent Genetics RCV000763221 SCV000893848 pathogenic Macrocephaly/autism syndrome; Meningioma, familial; Malignant tumor of prostate; VACTERL association with hydrocephalus; Glioma susceptibility 2; PTEN hamartoma tumor syndrome; Cowden syndrome 1 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000169890 SCV000222220 pathogenic not provided 2018-10-11 criteria provided, single submitter clinical testing The R173C missense variant in the PTEN gene has been reported previously in association with both familial and de novo PTEN-hamartoma tumor syndrome (for examples, see Lachlan et al., 2007; Tan et al., 2007; Hopman et al., 2012). Functional studies show that R173C significantly decreases phosphatase activity compared to the wild-type (Han et al., 2000). The R173C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across species. Missense variants in the same residue (R173H, R173P), as well as variants in nearby residues, have been reported in individuals suspicious for PTEN-hamartoma tumor syndrome, supporting the functional importance of this region of the protein (Lachlan et al., 2007; Kirches et al., 2010). Based on the currently available evidence, we consider R173C to be pathogenic.
Herman Laboratory,Nationwide Children's Hospital RCV000490574 SCV000579278 pathogenic PTEN hamartoma tumor syndrome 2017-03-01 criteria provided, single submitter clinical testing
Invitae RCV000490574 SCV000645594 pathogenic PTEN hamartoma tumor syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 173 of the PTEN protein (p.Arg173Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs121913293, ExAC no frequency). This variant has been reported in several individuals affected with PTEN Hamartoma Tumor Syndrome  (PMID: 17526800, 25669429, 24778394, 22628360). This variant has also been shown to arise de novo in an individual affected with PTEN Hamartoma Tumor Syndrome (PMID: 17526800). ClinVar contains an entry for this variant (Variation ID: 189500). Experimental studies in E. coli have shown that this missense change abolishes the phosphatase activity of the PTEN protein (PMID: 10866302). For these reasons, this variant has been classified as Pathogenic.

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