Submissions for variant NM_006231.4(POLE):c.840A>C (p.Lys280Asn)

dbSNP: rs908089476

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564053	SCV000671498	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-31	criteria provided, single submitter	clinical testing	The p.K280N variant (also known as c.840A>C), located in coding exon 9 of the POLE gene, results from an A to C substitution at nucleotide position 840. The lysine at codon 280 is replaced by asparagine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001591339	SCV000958443	uncertain significance	not provided	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 280 of the POLE protein (p.Lys280Asn). This variant is not present in population databases (gnomAD no frequency). 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: 484477). 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.
GeneDx	RCV001591339	SCV001823320	uncertain significance	not provided	2021-03-23	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); 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
Sema4, Sema4	RCV000564053	SCV002536946	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-21	criteria provided, single submitter	curation
Baylor Genetics	RCV000817860	SCV004203558	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-06-22	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV001249373	SCV001423364	not provided	Polymerase proofreading associated polyposis		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 10-10-2017 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
PreventionGenetics, part of Exact Sciences	RCV004530616	SCV004716050	uncertain significance	POLE-related disorder	2024-01-03	no assertion criteria provided	clinical testing	The POLE c.840A>C variant is predicted to result in the amino acid substitution p.Lys280Asn. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/484477/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.