ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.1171C>T (p.Pro391Ser) (rs786203911)

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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 RCV000538790 SCV000840495 uncertain significance PTEN hamartoma tumor syndrome 2017-11-08 reviewed by expert panel curation PTEN c.1171C>T (p.P391S) is currently classified as a variant of uncertain significance 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). PM2: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (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.
Ambry Genetics RCV000167422 SCV000218278 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000212888 SCV000222170 uncertain significance not specified 2017-05-05 criteria provided, single submitter clinical testing This variant is denoted PTEN c.1171C>T at the cDNA level, p.Pro391Ser (P391S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PTEN Pro391Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PTEN Pro391Ser occurs at a position that is conserved across species and is not located in a known functional domain (Nguyen 2014, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PTEN Pro391Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000585009 SCV000232946 uncertain significance not provided 2015-04-17 criteria provided, single submitter clinical testing
Invitae RCV000538790 SCV000645550 uncertain significance PTEN hamartoma tumor syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 391 of the PTEN protein (p.Pro391Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PTEN-related disease. ClinVar contains an entry for this variant (Variation ID: 187673). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585009 SCV000692694 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing

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