ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2106G>T (p.Gly702=)

gnomAD frequency: 0.00198  dbSNP: rs5744801
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001079677 SCV000289289 benign Colorectal cancer, susceptibility to, 12 2021-12-12 criteria provided, single submitter clinical testing
GeneDx RCV000759273 SCV000521366 likely benign not provided 2022-05-11 criteria provided, single submitter clinical testing See Variant Classification Assertion Criteria.
Ambry Genetics RCV000572802 SCV000671308 likely benign Hereditary cancer-predisposing syndrome 2015-08-12 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics,PreventionGenetics RCV000444253 SCV000806740 benign not specified 2017-08-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759273 SCV000888508 benign not provided 2018-09-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000444253 SCV001361240 benign not specified 2019-04-25 criteria provided, single submitter clinical testing Variant summary: POLE c.2106G>T alters a non-conserved nucleotide resulting in a synonymous change. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00055 in 250120 control chromosomes, predominantly at a frequency of 0.0074 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 521 fold of 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 or African-American origin. To our knowledge, no occurrence of c.2106G>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (2x) /likely benign (4x). Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory,University of Chicago RCV000444253 SCV002067057 likely benign not specified 2021-06-07 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000572802 SCV000805294 likely benign Hereditary cancer-predisposing syndrome 2018-04-27 no assertion criteria provided clinical testing

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