Submissions for variant NM_006231.4(POLE):c.5572C>T (p.Arg1858Cys)

gnomAD frequency: 0.00001  dbSNP: rs1193081581

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000759309	SCV000653380	uncertain significance	not provided	2024-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1858 of the POLE protein (p.Arg1858Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 473745). 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 expected to disrupt POLE protein function with a positive 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	RCV000759309	SCV000888559	uncertain significance	not provided	2018-07-16	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268163	SCV002550058	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003159915	SCV003893301	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-23	criteria provided, single submitter	clinical testing	The p.R1858C variant (also known as c.5572C>T), located in coding exon 41 of the POLE gene, results from a C to T substitution at nucleotide position 5572. The arginine at codon 1858 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000759309	SCV005080824	uncertain significance	not provided	2024-01-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 28481359, 29056344)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV005055124	SCV005689217	uncertain significance	Colorectal cancer, susceptibility to, 12	2025-02-05	criteria provided, single submitter	clinical testing	The POLE c.5572C>T (p.Arg1858Cys) missense change has a maximum subpopulation frequency of 0.0.0056% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.