ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.2683G>A (p.Ala895Thr) (rs201115064)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569257 SCV000671313 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
Counsyl RCV000472688 SCV000785069 uncertain significance Colorectal cancer, susceptibility to, 12 2017-03-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765065 SCV000896262 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism, immunodeficiency, livedo, and short stature 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000657053 SCV000322161 uncertain significance not provided 2018-12-11 criteria provided, single submitter clinical testing This variant is denoted POLE c.2683G>A at the cDNA level, p.Ala895Thr (A895T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC). This variant was reported in at least two individuals with an attenuated polyposis phenotype, but no reported family history, and has been observed in a family with an autism spectrum disorder (Cukier 2014, Spier 2014). POLE Ala895Thr was observed at an allele frequency of 0.06% (15/25,788) in individuals of Finnish ancestry in large population cohorts (Lek 2016). POLE Ala895Thr is located in the polymerase domain (Preston 2010). In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether POLE Ala895Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000255380 SCV000596499 uncertain significance not specified 2017-04-03 criteria provided, single submitter clinical testing
Invitae RCV000472688 SCV000543990 uncertain significance Colorectal cancer, susceptibility to, 12 2018-06-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 895 of the POLE protein (p.Ala895Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs201115064, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with attenuated polyposis (PMID: 25529843). ClinVar contains an entry for this variant (Variation ID: 265355). 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: "Probably Damaging"; 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000255380 SCV000712561 uncertain significance not specified 2016-11-15 criteria provided, single submitter clinical testing The p.Ala895Thr variant in POLE has been reported in 2 individuals with colorect al adenomatous polyposis with an attenuated phenotype (Spier 2015). This variant has also been identified in 47/66724 of European chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201115064). Com putational prediction tools and conservation analysis suggest that the p.Ala895T hr variant may impact the protein, though this information is not predictive eno ugh to determine pathogenicity. In summary, the clinical significance of the p.A la895Thr variant is uncertain.
Mendelics RCV000709264 SCV000838695 uncertain significance Familial colorectal cancer 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255380 SCV000602013 uncertain significance not specified 2017-04-18 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000569257 SCV000788171 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-12 no assertion criteria provided clinical testing

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