Submissions for variant NM_006231.4(POLE):c.1574A>G (p.Asn525Ser)

gnomAD frequency: 0.00004  dbSNP: rs74878897

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567336	SCV000671410	likely benign	Hereditary cancer-predisposing syndrome	2024-12-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003655127	SCV000825591	uncertain significance	not provided	2024-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 525 of the POLE protein (p.Asn525Ser). This variant is present in population databases (rs74878897, gnomAD 0.03%). 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: 484455). 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.
GeneDx	RCV003655127	SCV005443467	uncertain significance	not provided	2024-07-03	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
PreventionGenetics, part of Exact Sciences	RCV004737842	SCV005353585	uncertain significance	POLE-related disorder	2024-03-11	no assertion criteria provided	clinical testing	The POLE c.1574A>G variant is predicted to result in the amino acid substitution p.Asn525Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/484455/). Alternative variant at the same codon p.Asn525Asp has been observed in patient with colorectal cancer with microsatellite instability (Table S2, Chang et al 2020. PubMed ID: 431769227). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.