Submissions for variant NM_006231.4(POLE):c.664C>G (p.Arg222Gly)

dbSNP: rs767503360

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486962	SCV000570805	uncertain significance	not provided	2016-06-27	criteria provided, single submitter	clinical testing	This variant is denoted POLE c.664C>G at the cDNA level, p.Arg222Gly (R222G) at the protein level, and results in the change of an Arginine to a Glycine (CGC>GGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Arg222Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. POLE Arg222Gly occurs at a position that is conserved across species and is not located in a known functional domain (Tahirov 2009, Preston 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether POLE Arg222Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000486962	SCV001534782	uncertain significance	not provided	2020-10-21	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 421556). This sequence change replaces arginine with glycine at codon 222 of the POLE protein (p.Arg222Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine.
Ambry Genetics	RCV002367641	SCV002663250	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-13	criteria provided, single submitter	clinical testing	The p.R222G variant (also known as c.664C>G), located in coding exon 7 of the POLE gene, results from a C to G substitution at nucleotide position 664. The arginine at codon 222 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.