Submissions for variant NM_006231.4(POLE):c.6445C>T (p.Arg2149Cys)

gnomAD frequency: 0.00004  dbSNP: rs771490182

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000995008	SCV000544019	likely benign	not provided	2025-02-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000709240	SCV000838671	uncertain significance	Familial colorectal cancer	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765044	SCV000896241	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000995008	SCV001148873	uncertain significance	not provided	2018-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000995008	SCV001814606	uncertain significance	not provided	2021-01-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000476996	SCV002584930	uncertain significance	Colorectal cancer, susceptibility to, 12	2022-10-03	criteria provided, single submitter	clinical testing	The POLE c.6445C>T (p.Arg2149Cys) missense change has a maximum subpopulation frequency of 0.059% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign 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.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV003151773	SCV003839158	uncertain significance	Polymerase proofreading-related adenomatous polyposis		criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 46 of the POLE gene that results in the amino acid substitution of Cystine for Arginine at codon 2149 was detected. The observed variant c.6445C>T (p.Arg2149Cys) not been reported in 1000 genomes and has MAF of 0.01% in gnomAD databases. The in silico prediction of the variant is disease causing by MutationTaster2 and CADD. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000476996	SCV004015274	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing	A variant of uncertain significance was detected at POLE gene (c.6445C>T). This sequence change replaces arginine with cysteine at codon 2149 of the POLE protein (p.Arg2149Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs771490182, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with POLE-related disease. ClinVar contains an entry for this variant (Variation ID: 405704). In-silico predictions show benign computational verdict based on 8 benign predictions from BayesDel_addAF, DEOGEN2, EIGEN, M-CAP, MVP, MutationAssessor, PrimateAI and SIFT vs 4 pathogenic predictions from DANN, FATHMM-MKL, LIST-S2 and MutationTaster but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321601	SCV004027288	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004943853	SCV005479471	likely benign	Hereditary cancer-predisposing syndrome	2024-07-30	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.