ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6271C>T (p.Pro2091Ser)

dbSNP: rs572252265
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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 RCV000760032 SCV000653430 uncertain significance not provided 2024-12-19 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2091 of the POLE protein (p.Pro2091Ser). This variant is present in population databases (rs572252265, gnomAD 0.06%). 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: 473789). 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%. 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 RCV000760032 SCV000889782 likely benign not provided 2017-12-27 criteria provided, single submitter clinical testing
GeneDx RCV000760032 SCV002526269 uncertain significance not provided 2022-06-08 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Neuberg Centre For Genomic Medicine, NCGM RCV004555586 SCV005044769 uncertain significance Colorectal cancer, susceptibility to, 12 criteria provided, single submitter clinical testing The missense c.6271C>T p.Pro2091Ser variant in the POLE gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is novel not in any individuals in gnomAD Exomes and 1000 Genom This variant is reported with the allele frequency 0.007% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Proline at position 2091 is changed to a Serine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Pro2091Ser in POLE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV005004238 SCV005633666 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency 2024-04-29 criteria provided, single submitter clinical testing

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