ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.521A>G (p.Tyr174Cys) (rs864622341)

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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 RCV000204849 SCV000840459 likely pathogenic PTEN hamartoma tumor syndrome 2018-09-26 reviewed by expert panel curation PTEN c.521A>G (p.Y174C) meets criteria to be classified as likely 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: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000602123.1) PM2: Absent in large sequenced populations (PMID 27535533). 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. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (Internal laboratory contributor(s) SCV000602123.1)
Invitae RCV000204849 SCV000260225 likely pathogenic PTEN hamartoma tumor syndrome 2020-03-19 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 174 of the PTEN protein (p.Tyr174Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Bannayan-Riley-Ruvalcaba syndrome (external communication). ClinVar contains an entry for this variant (Variation ID: 220007). 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.
GeneDx RCV000507056 SCV000569688 likely pathogenic not provided 2018-04-04 criteria provided, single submitter clinical testing This variant is denoted PTEN c.521A>G at the cDNA level, p.Tyr174Cys (Y174C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a metastatic melanoma lesion (Wang 2010). Additionally, a different missense variant at the same residue, PTEN Tyr174Asn, demonstrated loss of phosphatase activity in an in vitro assay (Han 2000). PTEN Tyr174Cys was not observed in large population cohorts (Lek 2016). This variant is located in the Phosphatase domain (Molinari 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence and internal data, we consider PTEN Tyr174Cys to be likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507056 SCV000602123 pathogenic not provided 2017-06-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562262 SCV000664914 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-13 criteria provided, single submitter clinical testing The p.Y174C variant (also known as c.521A>G), located in coding exon 6 of the PTEN gene, results from an A to G substitution at nucleotide position 521. The tyrosine at codon 174 is replaced by cysteine, an amino acid with highly dissimilar properties. While this exact alteration has not been reported in the literature to date, an alteration at the same codon, p.Y174N (c.520T>A), has been reported in an in vitro functional analysis, and demonstrated abolished protein phosphatase activity (Han S et al. Cancer Res. 2000 Jun 15;60(12):3147-51). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic RCV000485478 SCV000692015 uncertain significance not specified no assertion criteria provided clinical testing

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