Submissions for variant NM_006231.4(POLE):c.4012G>A (p.Glu1338Lys)

gnomAD frequency: 0.00001  dbSNP: rs751555395

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001569979	SCV000544135	uncertain significance	not provided	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1338 of the POLE protein (p.Glu1338Lys). This variant is present in population databases (rs751555395, gnomAD 0.007%). 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: 405810). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000608100	SCV000712815	uncertain significance	not specified	2017-02-06	criteria provided, single submitter	clinical testing	The p.Glu1338Lys variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 1/11246 of Latino chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs751555395). Computational prediction tools and conservation analysis sugges t that the p.Glu1338Lys variant may not impact the protein, though this informat ion is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Glu1338Lys variant is uncertain.
GeneDx	RCV001569979	SCV001794162	uncertain significance	not provided	2023-02-21	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002356661	SCV002622199	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-12	criteria provided, single submitter	clinical testing	The p.E1338K variant (also known as c.4012G>A), located in coding exon 32 of the POLE gene, results from a G to A substitution at nucleotide position 4012. The glutamic acid at codon 1338 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. 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 this alteration remains unclear.