ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.1280C>T (p.Ala427Val) (rs878854841)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233203 SCV000289248 uncertain significance Colorectal cancer, susceptibility to, 12 2019-12-22 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 427 of the POLE protein (p.Ala427Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual undergoing hereditary cancer screening (PMID: 27720647). ClinVar contains an entry for this variant (Variation ID: 240385). 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.
Ambry Genetics RCV000568911 SCV000671233 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000728878 SCV000856497 uncertain significance not provided 2017-08-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825439 SCV000966737 uncertain significance not specified 2018-10-18 criteria provided, single submitter clinical testing The p.Ala427Val variant in POLE has been reported in one individual who underwen t genetic testing for hereditary cancer (Mu 2016). This variant has also been re ported by other clinical laboratories in ClinVar (Variation ID: 240385) and has been identified in 2/126678 European chromosomes by gnomAD (http://gnomad.broadi nstitute.org). Computational prediction tools and conservation analysis do not p rovide strong support for or against an impact to the protein. In summary, the c linical significance of the p.Ala427Val variant is uncertain. ACMG/AMP Criteria applied: PM2.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000728878 SCV001134677 uncertain significance not provided 2019-08-04 criteria provided, single submitter clinical testing

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