Submissions for variant NM_006231.4(POLE):c.6508T>C (p.Cys2170Arg)

gnomAD frequency: 0.00004  dbSNP: rs138094751

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000985992	SCV000653447	uncertain significance	not provided	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 2170 of the POLE protein (p.Cys2170Arg). This variant is present in population databases (rs138094751, 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: 473804). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLE protein function. 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	RCV000985992	SCV001134750	uncertain significance	not provided	2019-07-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000985992	SCV001148870	uncertain significance	not provided	2018-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000985992	SCV002601337	uncertain significance	not provided	2023-05-17	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; This variant is associated with the following publications: (PMID: 19296856)
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003989560	SCV004807319	uncertain significance	Colorectal cancer, susceptibility to, 12	2024-03-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004944009	SCV005478806	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-06	criteria provided, single submitter	clinical testing	The p.C2170R variant (also known as c.6508T>C), located in coding exon 46 of the POLE gene, results from a T to C substitution at nucleotide position 6508. The cysteine at codon 2170 is replaced by arginine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004737827	SCV005348366	uncertain significance	POLE-related disorder	2024-03-26	no assertion criteria provided	clinical testing	The POLE c.6508T>C variant is predicted to result in the amino acid substitution p.Cys2170Arg. This variant has been reported in an individual with colorectal cancer, who also had a nonsense variant in MSH6, and missense variants in POLE and CDH1 (Supplementary Table 3 in Bhai et al 2021. PubMed ID: 34326862). This variant is reported in 0.0057% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/473804/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.