ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.1061C>A (p.Pro354Gln) (rs375709098)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000205690 SCV000886865 uncertain significance PTEN hamartoma tumor syndrome 2018-11-28 reviewed by expert panel curation PTEN c.1061C>A (p.Pro354Gln) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). 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. BS3: Missense variants with both lipid phosphatase activity AND results from a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. (PMID 29706350, 29785012)
Ambry Genetics RCV000132539 SCV000187636 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000513025 SCV000222169 uncertain significance not provided 2018-08-07 criteria provided, single submitter clinical testing This variant is denoted PTEN c.1061C>A at the cDNA level, p.Pro354Gln (P354Q) at the protein level, and results in the change of a Proline to a Glutamine (CCG>CAG). Mester et al. (2011) reported this variant occurring in two related individuals with features of Cowden syndrome, however neither met International Cowden Syndrome Consortium diagnostic criteria. Pilarski et al. (2011) reported an additional patient with this variant identified through clinical PTEN testing. Yurgelun et al. (2015) identified this variant in an individual undergoing multi-gene cancer panel testing based on a history of a Lynch syndrome-related cancer and/or polyps; this particular individual was also found to harbor a pathogenic MSH2 variant. Lastly, this variant was observed in an individual with neuroblastoma and in an individual with a personal and family history of breast cancer (Zhang 2015, Caminsky 2016). PTEN Pro354Gln was observed at an allele frequency of 0.016% (19/122,896) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the C-terminal domain (Wang 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PTEN Pro354Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000205690 SCV000260548 uncertain significance PTEN hamartoma tumor syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces proline with glutamine at codon 354 of the PTEN protein (p.Pro354Gln). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and glutamine. This variant is present in population databases (rs375709098, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with Cowden syndrome (PMID: 21194675, 21659347, 21343951), neuroblastoma (PMID: 26580448), and suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 143020). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000210607 SCV000263012 uncertain significance Inborn genetic diseases 2015-10-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Counsyl RCV000409006 SCV000488776 uncertain significance Cowden syndrome 1 2016-06-14 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513025 SCV000608561 uncertain significance not provided 2017-03-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000513025 SCV000696524 uncertain significance not provided 2015-11-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000513025 SCV000704628 uncertain significance not provided 2016-12-13 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000201314 SCV000711737 uncertain significance not specified 2018-10-08 criteria provided, single submitter clinical testing The p.Pro354Gln variant in PTEN has been reported in 6 individuals with a clinic al diagnosis or features of PTEN hamartoma tumor syndrome and segregated with di sease in at least 1 affected relative (Mester 2011, Pilarski 2011, Tan 2011, Niz ialek 2015, Zhang 2015, Caminsky 2016). This variant was also reported in 1 indi vidual with features of Lynch syndrome, who also carried a pathogenic variant in MSH2 (Yurgelun 2015). Other clinical laboratories have reported this variant in ClinVar (Variation ID: 143020). It has also been identified in 21/270810 Europe an chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational predi ction tools and conservation analysis do not provide strong support for or again st an impact to the protein. In summary, the clinical significance of the p.Pro3 54Gln variant is uncertain. ACMG/AMP criteria applied: PS4_Moderate, BP5.
PreventionGenetics,PreventionGenetics RCV000513025 SCV000806058 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000513025 SCV000889800 uncertain significance not provided 2017-12-14 criteria provided, single submitter clinical testing
Color RCV000132539 SCV000910731 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-22 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000201314 SCV000692023 uncertain significance not specified no assertion criteria provided clinical testing

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