Submissions for variant NM_006231.4(POLE):c.154C>T (p.Arg52Trp)

gnomAD frequency: 0.00016  dbSNP: rs115452881

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000759976	SCV000289259	uncertain significance	not provided	2025-01-23	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 52 of the POLE protein (p.Arg52Trp). This variant is present in population databases (rs115452881, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596, 35534704). ClinVar contains an entry for this variant (Variation ID: 240396). 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.
Mendelics	RCV003492006	SCV000838711	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759976	SCV000889709	uncertain significance	not provided	2017-10-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763823	SCV000894740	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000232236	SCV001481315	uncertain significance	Colorectal cancer, susceptibility to, 12	2020-12-13	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000759976	SCV002522123	uncertain significance	not provided	2024-10-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30849372, 35264596, 35534704)
Sema4, Sema4	RCV000758172	SCV002536756	likely benign	Hereditary cancer-predisposing syndrome	2020-10-12	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000232236	SCV002584674	uncertain significance	Colorectal cancer, susceptibility to, 12	2022-09-28	criteria provided, single submitter	clinical testing	The POLE c.154C>T (p.Arg52Trp) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000759976	SCV004226398	uncertain significance	not provided	2022-06-30	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493544	SCV004243026	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000759976	SCV005197247	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000758172	SCV005481529	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-23	criteria provided, single submitter	clinical testing	The p.R52W variant (also known as c.154C>T), located in coding exon 2 of the POLE gene, results from a C to T substitution at nucleotide position 154. The arginine at codon 52 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly 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	RCV005008189	SCV005633784	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	2024-02-01	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000758172	SCV000886708	uncertain significance	Hereditary cancer-predisposing syndrome	2018-09-12	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532918	SCV004719996	uncertain significance	POLE-related disorder	2023-12-05	no assertion criteria provided	clinical testing	The POLE c.154C>T variant is predicted to result in the amino acid substitution p.Arg52Trp. This variant has been reported in a cohort of individuals with a history breast cancer, but was interpreted as uncertain (Supplementary Table 3, Guindalini et al. 2022. PubMed ID: 35264596). This variant is reported in 0.025% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/240396/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.