ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.2599G>A (p.Val867Ile) (rs374200895)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234141 SCV000289300 uncertain significance Colorectal cancer, susceptibility to, 12 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 867 of the POLE protein (p.Val867Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs374200895, ExAC 0.007%). This variant has not been reported in the literature in individuals with POLE-related disease. ClinVar contains an entry for this variant (Variation ID: 240436). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000657131 SCV000569879 uncertain significance not provided 2018-03-14 criteria provided, single submitter clinical testing This variant is denoted POLE c.2599G>A at the cDNA level, p.Val867Ile (V867I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). Although this variant has not, to our knowledge, been published in the literature as a germline variant, it has been reported as a somatic variant in a medulloblastoma tumor (Kool 2014). POLE Val867Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in polymerase domain (Preston 2010). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether POLE Val867Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657131 SCV000602008 uncertain significance not provided 2019-06-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563337 SCV000671335 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-03 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000657131 SCV001148896 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing

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