ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.3245G>A (p.Arg1082His) (rs201744227)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232058 SCV000289325 uncertain significance Colorectal cancer, susceptibility to, 12 2019-12-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1082 of the POLE protein (p.Arg1082His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs201744227, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with colorectal cancer (PMID: 29987844). ClinVar contains an entry for this variant (Variation ID: 240461). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.
GeneDx RCV000484837 SCV000568952 uncertain significance not provided 2018-05-24 criteria provided, single submitter clinical testing This variant is denoted POLE c.3245G>A at the cDNA level, p.Arg1082His (R1082H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Arg1082His was observed at an allele frequency of 0.026% (33/125928) in individuals of European ancestry in large population cohorts (Lek 2016). POLE Arg1082His is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether POLE Arg1082His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484837 SCV000888523 uncertain significance not provided 2019-01-25 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825438 SCV000966736 uncertain significance not specified 2018-10-18 criteria provided, single submitter clinical testing The p.Arg1082His variant in POLE has not been previously reported in the literat ure in individuals with colorectal cancer but has been reported by other clinica l laboratories in ClinVar (Variation ID: 240461). This variant has also been ide ntified in 33/125928 of European chromosomes by gnomAD (http://gnomad.broadinsti Computational prediction tools do not provide support for or against an impact to the protein. In summary, the clinical significance of the p.Arg1082 His variant is uncertain. ACMG/AMP Criteria applied: None applicable.
True Health Diagnostics RCV000758174 SCV000886711 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-12 no assertion criteria provided clinical testing

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