Submissions for variant NM_006231.4(POLE):c.863C>G (p.Ala288Gly)

gnomAD frequency: 0.00004  dbSNP: rs771619667

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507034	SCV000602103	uncertain significance	not specified	2017-06-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000574444	SCV000671503	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-07	criteria provided, single submitter	clinical testing	The p.A288G variant (also known as c.863C>G), located in coding exon 9 of the POLE gene, results from a C to G substitution at nucleotide position 863. The alanine at codon 288 is replaced by glycine, an amino acid with similar properties. This amino acid position is well 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001577563	SCV000818720	uncertain significance	not provided	2024-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 288 of the POLE protein (p.Ala288Gly). This variant is present in population databases (rs771619667, gnomAD 0.01%). 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: 439282). 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 expected to disrupt POLE protein function with a positive predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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	RCV001577563	SCV001804963	uncertain significance	not provided	2022-05-12	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)
Sema4, Sema4	RCV000574444	SCV002536951	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-27	criteria provided, single submitter	curation
Baylor Genetics	RCV000690986	SCV004203512	uncertain significance	Colorectal cancer, susceptibility to, 12	2024-03-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737580	SCV005357530	uncertain significance	POLE-related disorder	2024-03-28	no assertion criteria provided	clinical testing	The POLE c.863C>G variant is predicted to result in the amino acid substitution p.Ala288Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD, and is classified as uncertain by numerous labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/439282/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.