Submissions for variant NM_006231.4(POLE):c.1184G>A (p.Gly395Glu)

gnomAD frequency: 0.00022  dbSNP: rs546499094

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236289	SCV000294047	uncertain significance	not provided	2023-04-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colon cancer (Siraj et al., 2020); This variant is associated with the following publications: (PMID: 20951805, 32567205, 36479248)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000236289	SCV000544207	uncertain significance	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 395 of the POLE protein (p.Gly395Glu). This variant is present in population databases (rs546499094, gnomAD 0.07%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 32567205). ClinVar contains an entry for this variant (Variation ID: 246477). 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.
Ambry Genetics	RCV000561443	SCV000671429	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-19	criteria provided, single submitter	clinical testing	The p.G395E variant (also known as c.1184G>A), located in coding exon 12 of the POLE gene, results from a G to A substitution at nucleotide position 1184. The glycine at codon 395 is replaced by glutamic acid, an amino acid with similar properties. This alteration was identified in an individual diagnosed with colorectal cancer from the Middle East (Siraj AK et al. Mol Genet Genomic Med, 2020 08;8:e1368). This amino acid position is highly conserved in available vertebrate species. 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.
Revvity Omics, Revvity	RCV000236289	SCV003809192	uncertain significance	not provided	2022-03-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236289	SCV004219072	likely benign	not provided	2022-10-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004567791	SCV005056550	uncertain significance	Colorectal cancer, susceptibility to, 12	2024-01-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535199	SCV004120005	uncertain significance	POLE-related disorder	2024-07-12	no assertion criteria provided	clinical testing	The POLE c.1184G>A variant is predicted to result in the amino acid substitution p.Gly395Glu. This variant has been reported in two individuals with colorectal cancer or breast cancer (Siraj et al. 2020. PubMed ID: 32567205; Table S3, de Oliveira et al. 2022. PubMed ID: 35534704). This variant is reported in 0.068% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/246477/). This variant resides in the exonuclease domain of the POLE protein (Palles et al. 2013. PubMed ID: 23263490; Mur et al. 2020. PubMed ID: 32792570). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.