Submissions for variant NM_006231.4(POLE):c.4244A>G (p.Asn1415Ser)

dbSNP: rs748378612

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235660	SCV000293811	uncertain significance	not provided	2016-01-12	criteria provided, single submitter	clinical testing	This variant is denoted POLE c.4244A>G at the cDNA level, p.Asn1415Ser (N1415S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Asn1415Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. POLE Asn1415Ser occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether POLE Asn1415Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000235660	SCV000653279	uncertain significance	not provided	2024-11-24	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 1415 of the POLE protein (p.Asn1415Ser). This variant is present in population databases (rs748378612, 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: 246313). 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.
Counsyl	RCV000530706	SCV000786450	uncertain significance	Colorectal cancer, susceptibility to, 12	2018-05-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002327165	SCV002632864	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-13	criteria provided, single submitter	clinical testing	The p.N1415S variant (also known as c.4244A>G), located in coding exon 33 of the POLE gene, results from an A to G substitution at nucleotide position 4244. The asparagine at codon 1415 is replaced by serine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.