ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.2561+6T>C (rs116231808)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000759989 SCV000261421 benign not provided 2019-03-06 criteria provided, single submitter clinical testing
GeneDx RCV000418464 SCV000518902 likely benign not specified 2017-09-25 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000418464 SCV000602007 likely benign not specified 2017-04-21 criteria provided, single submitter clinical testing
Counsyl RCV000205075 SCV000786047 likely benign Colorectal cancer, susceptibility to, 12 2018-02-16 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759989 SCV000889729 benign not provided 2018-05-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000418464 SCV000920073 benign not specified 2018-04-06 criteria provided, single submitter clinical testing Variant summary: POLE c.2561+6T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Five computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was observed with an allele frequency of 0.0005816 in 276802 control chromosomes, predominantly in the African cohort, 153/24000 chromosomes. The observed variant frequency within African control individuals in the gnomAD database is approximately 450-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.2561+6T>C in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign.

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