ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.4246G>A (p.Ala1416Thr) (rs146711942)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001080892 SCV000289372 benign Colorectal cancer, susceptibility to, 12 2019-12-28 criteria provided, single submitter clinical testing
GeneDx RCV000657118 SCV000569314 uncertain significance not provided 2018-01-22 criteria provided, single submitter clinical testing This variant is denoted POLE c.4246G>A at the cDNA level, p.Ala1416Thr (A1416T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). This variant has been reported in at least one individual with an unspecified advanced cancer, undergoing multi-gene panel testing (Mandelker 2017). POLE Ala1416Thr was observed at an allele frequency of 0.5% in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 POLE Ala1416Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478006 SCV000602045 uncertain significance not specified 2017-05-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000564865 SCV000671255 likely benign Hereditary cancer-predisposing syndrome 2015-06-19 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768288 SCV000898892 uncertain significance Facial dysmorphism, immunodeficiency, livedo, and short stature 2018-09-12 criteria provided, single submitter clinical testing POLE NM_006231.3 exon 33 p.Ala1416Thr (c.4246G>A): This variant has been reported in the literature in at least 1 individual with unspecified advanced cancer (Mandelker 2017 PMID:28873162). This variant is present in 0.4% (47/10152) of Ashkenazi Jewish alleles in the Genome Aggregation Database ( and is present in ClinVar (Variation ID:240508). This variant amnio acid Threonine (Thr) is present in >40 species, including mammals. This suggests that this variant may not impact the protein. Additional computational prediction tools also do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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