ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.5900C>T (p.Ala1967Val) (rs201273415)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235266 SCV000293742 uncertain significance not provided 2018-10-03 criteria provided, single submitter clinical testing This variant is denoted POLE c.5900C>T at the cDNA level, p.Ala1967Val (A1967V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). Although this variant has not, to our knowledge, been published in the literature as a germline variant, it has been reported as a confirmed somatic variant in uterine serous carcinoma and metastatic melanoma (Zhao 2013, Van Allen 2014). POLE Ala1967Val was observed at an allele frequency of 0.045% (15/33578) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Ala1967Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000461742 SCV000543923 uncertain significance Colorectal cancer, susceptibility to, 12 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1967 of the POLE protein (p.Ala1967Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs201273415, ExAC 0.1%), 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 a POLE-related disease. ClinVar contains an entry for this variant (Variation ID: 246263). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
PreventionGenetics,PreventionGenetics RCV000235266 SCV000806821 uncertain significance not provided 2017-02-24 criteria provided, single submitter clinical testing
Mendelics RCV000461742 SCV001138859 likely benign Colorectal cancer, susceptibility to, 12 2019-05-28 criteria provided, single submitter clinical testing

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