ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.2236A>G (p.Ile746Val) (rs1480527153)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000780644 SCV000918087 uncertain significance not specified 2018-07-10 criteria provided, single submitter clinical testing Variant summary: POLE c.2236A>G (p.Ile746Val) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246264 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2236A>G in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000792678 SCV000931988 uncertain significance Colorectal cancer, susceptibility to, 12 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 746 of the POLE protein (p.Ile746Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with POLE-related disease. ClinVar contains an entry for this variant (Variation ID: 632958). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Mendelics RCV000792678 SCV001138892 uncertain significance Colorectal cancer, susceptibility to, 12 2019-05-28 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.