ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.857C>G (p.Pro286Arg) (rs1057519943)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Database of Curated Mutations (DoCM) RCV000443524 SCV000507146 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427424 SCV000507147 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437655 SCV000507148 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443610 SCV000507149 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426701 SCV000507150 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Invitae RCV000532834 SCV000653485 uncertain significance Colorectal cancer, susceptibility to, 12 2017-02-01 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 286 of the POLE protein (p.Pro286Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in the germline of individuals with a POLE-related disease, however, it has been reported as a frequent somatic change in endometrial and colorectal cancers (PMID: 23263490, 23447401, 25224212, 24525744). This variant is located within the evolutionarily conserved exonuclease domain of the POLE protein (PMID: 23447401, 24525744). Experimental studies have shown that the P301R yeast mutant, corresponding to the p.Pro286Arg change, severely affects the fidelity rather than the proofreading function of the POLE protein, causing a strong mutator phenotype in a yeast model system (PMID: 24525744). In addition, this variant showed a reduced 3'-5' exonuclease activity compared to the wild-type protein (PMID: 25228659). In summary, this variant is a rare missense change that is not present in the population and has been shown to affect protein function. Although this variant has been found as a frequent somatic event in tumors, it has not been observed in the germline of affected individuals. In the absence of genetic and/or additional evidence, this variant has been classified as Variant of Uncertain Significance.
Oxford Haemato-Oncology Service,Oxford University Hospitals NHS Foundation Trust RCV000626454 SCV000734844 drug response Anti-PDL1 response 2017-11-27 no assertion criteria provided clinical testing

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