Submissions for variant NM_006231.4(POLE):c.2053C>T (p.Arg685Trp)

gnomAD frequency: 0.00004  dbSNP: rs116326665

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003129861	SCV000543925	uncertain significance	not provided	2025-02-03	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 685 of the POLE protein (p.Arg685Trp). This variant is present in population databases (rs116326665, gnomAD 0.03%). 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: 405614). 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 not expected to disrupt POLE protein function with a negative 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.
Revvity Omics, Revvity	RCV003129861	SCV003809189	uncertain significance	not provided	2019-10-08	criteria provided, single submitter	clinical testing
GeneDx	RCV003129861	SCV003936374	uncertain significance	not provided	2023-12-10	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: 20951805)
CeGaT Center for Human Genetics Tuebingen	RCV003129861	SCV004136752	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357470	SCV001552951	uncertain significance	Polymerase proofreading-related adenomatous polyposis		no assertion criteria provided	clinical testing	The POLE p.Arg685Trp variant was not identified in the literature. The variant was identified in dbSNP (ID: rs116326665) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 18 of 269702 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23964 chromosomes (freq: 0.00004), European in 2 of 123376 chromosomes (freq: 0.00002), East Asian in 6 of 18674 chromosomes (freq: 0.0003), and South Asian in 9 of 29240 chromosomes (freq: 0.0003); it was not observed in the Other, Latino, Ashkenazi Jewish, and Finnish, populations. The p.Arg685 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.