Submissions for variant NM_006231.4(POLE):c.5036G>A (p.Arg1679His)

gnomAD frequency: 0.00001  dbSNP: rs748940418

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001547419	SCV001236329	uncertain significance	not provided	2024-11-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1679 of the POLE protein (p.Arg1679His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 863960). 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.
GeneDx	RCV001547419	SCV001767121	uncertain significance	not provided	2020-10-23	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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
Ambry Genetics	RCV002348484	SCV002646318	uncertain significance	Hereditary cancer-predisposing syndrome	2015-06-26	criteria provided, single submitter	clinical testing	The p.R1679H variant (also known as c.5036G>A), located in coding exon 38 of the POLE gene, results from a G to A substitution at nucleotide position 5036. The arginine at codon 1679 is replaced by histidine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.R1679H remains unclear.
Neuberg Centre For Genomic Medicine, NCGM	RCV001071047	SCV004047216	uncertain significance	Colorectal cancer, susceptibility to, 12		criteria provided, single submitter	clinical testing	The missense variant c.5036G>A (p.Arg1679His) in POLE gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database as Uncertain Significance. The p.Arg1679His variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.001855% is reported in gnomAD. The amino acid Arg at position 1679 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg1679His in POLE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004738155	SCV005349522	uncertain significance	POLE-related disorder	2024-08-16	no assertion criteria provided	clinical testing	The POLE c.5036G>A variant is predicted to result in the amino acid substitution p.Arg1679His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/863960/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.