ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6575C>T (p.Ala2192Val)

gnomAD frequency: 0.00004  dbSNP: rs756301031
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000679668 SCV000544172 uncertain significance not provided 2024-12-24 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2192 of the POLE protein (p.Ala2192Val). This variant is present in population databases (rs756301031, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 405847). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE protein function with a negative predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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, part of Exact Sciences RCV000679668 SCV000806843 uncertain significance not provided 2017-10-25 criteria provided, single submitter clinical testing
Baylor Genetics RCV001788223 SCV002030088 uncertain significance Facial dysmorphism-immunodeficiency-livedo-short stature syndrome 2021-04-29 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx RCV000679668 SCV002559518 uncertain significance not provided 2024-05-31 criteria provided, single submitter clinical testing In silico analysis indicates that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29056344, 19296856)
Ambry Genetics RCV002365616 SCV002665986 likely benign Hereditary cancer-predisposing syndrome 2022-09-24 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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