ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5002G>A (p.Gly1668Ser)

gnomAD frequency: 0.00003  dbSNP: rs371348453
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001591070 SCV000544164 uncertain significance not provided 2025-01-30 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1668 of the POLE protein (p.Gly1668Ser). This variant is present in population databases (rs371348453, 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: 405839). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507157 SCV000602060 uncertain significance not specified 2017-05-28 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000507157 SCV000712643 uncertain significance not specified 2016-11-17 criteria provided, single submitter clinical testing The p.Gly1668Ser variant in POLE has not been previously reported in individuals with colorectal cancer or in large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Gly1668Se r variant is uncertain.
Baylor Genetics RCV000469502 SCV001482620 uncertain significance Colorectal cancer, susceptibility to, 12 2020-02-11 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx RCV001591070 SCV001815190 uncertain significance not provided 2024-05-13 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on 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.; This variant is associated with the following publications: (PMID: 35534704, 32546565)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000507157 SCV002550077 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000469502 SCV003807543 uncertain significance Colorectal cancer, susceptibility to, 12 2022-06-10 criteria provided, single submitter clinical testing ACMG classification criteria: PM2 moderated, BP4 supporting
Ambry Genetics RCV000664294 SCV003893936 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-28 criteria provided, single submitter clinical testing The p.G1668S variant (also known as c.5002G>A), located in coding exon 38 of the POLE gene, results from a G to A substitution at nucleotide position 5002. The glycine at codon 1668 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
True Health Diagnostics RCV000664294 SCV000788181 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-01 no assertion criteria provided clinical testing

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