ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.844C>T (p.Pro282Ser) (rs138207610)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Department of Laboratory Medicine, University of Washington RCV000210101 SCV000266224 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000229770 SCV000289496 uncertain significance Colorectal cancer, susceptibility to, 12 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 282 of the POLE protein (p.Pro282Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs138207610, ExAC 0.02%). This variant has been reported in an individual affected with cutaneous malignant melanoma and Merkel cell carcinoma (PMID: 26251183) and an individual with familial colorectal cancer (PMID: 28195393), as well as an unaffected individual with a family history of breast cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224588). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. 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.
Counsyl RCV000229770 SCV000489555 uncertain significance Colorectal cancer, susceptibility to, 12 2016-10-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000210101 SCV000671436 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-04 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000607043 SCV000731304 uncertain significance not specified 2016-11-22 criteria provided, single submitter clinical testing The p.Pro282Ser variant in POLE has been reported in 1 individual with cutaneous malignant melanoma and 1 individual with breast cancer (Aoude 2015, Shirts 2016 ). It has also been identified in 10/66546 of European chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs138207610) . Computational prediction tools and conservation analysis suggest that the vari ant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro282Se r variant is uncertain.
PreventionGenetics,PreventionGenetics RCV000679671 SCV000806856 uncertain significance not provided 2017-12-08 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000735962 SCV000864151 uncertain significance Colorectal cancer 2015-09-01 criteria provided, single submitter research Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 37 year old female diagnosed with colon cancer at age 30. No family history of colorectal cancer or colon polyps. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679671 SCV000889794 uncertain significance not provided 2018-12-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000607043 SCV000920068 likely benign not specified 2019-11-05 criteria provided, single submitter clinical testing Variant summary: POLE c.844C>T (p.Pro282Ser) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family B, exonuclease domain (IPR006133) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 282822 control chromosomes, predominantly at a frequency of 0.00013 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9-fold the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.844C>T has been reported in the literature in individuals affected with colorectal cancer, breast cancer, and cutaneous melanoma (Hansen_2017, Shirts_2015, Aoude_2015). These reports do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and 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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