Submissions for variant NM_006231.4(POLE):c.895A>G (p.Met299Val)

gnomAD frequency: 0.00001  dbSNP: rs370727992

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001577089	SCV000653488	uncertain significance	not provided	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 299 of the POLE protein (p.Met299Val). This variant is present in population databases (rs370727992, gnomAD 0.003%). 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: 473838). 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%. 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	RCV000574558	SCV000671526	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-02	criteria provided, single submitter	clinical testing	The p.M299V variant (also known as c.895A>G), located in coding exon 9 of the POLE gene, results from an A to G substitution at nucleotide position 895. The methionine at codon 299 is replaced by valine, an amino acid with highly similar properties. 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.
GeneDx	RCV001577089	SCV001804414	uncertain significance	not provided	2022-07-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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)
Baylor Genetics	RCV000529210	SCV004203543	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-09-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004538071	SCV004114635	uncertain significance	POLE-related disorder	2024-03-07	no assertion criteria provided	clinical testing	The POLE c.895A>G variant is predicted to result in the amino acid substitution p.Met299Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 2 of ~21,000 alleles in gnomAD and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/473838/). This variant localizes to 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.