ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.3698G>A (p.Arg1233Gln) (rs201738371)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000540991 SCV000653231 uncertain significance Colorectal cancer, susceptibility to, 12 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1233 of the POLE protein (p.Arg1233Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs201738371, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with POLE-related disease. ClinVar contains an entry for this variant (Variation ID: 473616). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; 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.
Ambry Genetics RCV000575542 SCV000671423 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-01 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV001193002 SCV001361508 likely benign not specified 2019-10-28 criteria provided, single submitter clinical testing Variant summary: POLE c.3698G>A (p.Arg1233Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251428 control chromosomes. The observed variant frequency is approximately 5.3 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 benign. To our knowledge, no occurrence of c.3698G>A in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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