Submissions for variant NM_006231.4(POLE):c.2182C>T (p.Arg728Trp)

gnomAD frequency: 0.00001  dbSNP: rs1020252487

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003231583	SCV000819896	uncertain significance	not provided	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 728 of the POLE protein (p.Arg728Trp). 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: 571057). 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003231583	SCV002009595	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001816709	SCV002071941	uncertain significance	not specified	2021-10-11	criteria provided, single submitter	clinical testing	This sequence change does not appear to have been previously described in individuals with POLE-related disorders. This sequence change has been described in the gnomAD database in 2 individual which corresponds to a population frequency of 0.0058% (dbSNP rs1020252487). The p.Arg728Trp change affects a highly conserved amino acid residue located in a domain of the POLE protein that is known to be functional. The p.Arg728Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Arg728Trp change remains unknown at this time.
Ambry Genetics	RCV002424630	SCV002728521	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-09	criteria provided, single submitter	clinical testing	The p.R728W variant (also known as c.2182C>T), located in coding exon 20 of the POLE gene, results from a C to T substitution at nucleotide position 2182. The arginine at codon 728 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002485651	SCV002792977	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	2021-08-04	criteria provided, single submitter	clinical testing
GeneDx	RCV003231583	SCV003929788	uncertain significance	not provided	2024-04-26	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: 20951805)