Submissions for variant NM_006231.4(POLE):c.6065G>A (p.Ser2022Asn)

gnomAD frequency: 0.00001  dbSNP: rs905858506

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001558741	SCV000543959	uncertain significance	not provided	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 2022 of the POLE protein (p.Ser2022Asn). This variant is present in population databases (no rsID available, gnomAD 0.004%). 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: 405648). 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.
Baylor Genetics	RCV000476349	SCV001482621	uncertain significance	Colorectal cancer, susceptibility to, 12	2020-12-13	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001558741	SCV001780749	uncertain significance	not provided	2024-03-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed with POLE p.(Arg52Trp) in an individual with family history of colorectal, breast and other cancer in published literature (PMID: 35534704); This variant is associated with the following publications: (PMID: 35534704)
Ambry Genetics	RCV003168746	SCV003897946	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-27	criteria provided, single submitter	clinical testing	The p.S2022N variant (also known as c.6065G>A), located in coding exon 44 of the POLE gene, results from a G to A substitution at nucleotide position 6065. The serine at codon 2022 is replaced by asparagine, 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.
PreventionGenetics, part of Exact Sciences	RCV004533154	SCV004114765	uncertain significance	POLE-related disorder	2023-08-05	criteria provided, single submitter	clinical testing	The POLE c.6065G>A variant is predicted to result in the amino acid substitution p.Ser2022Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133209321-C-T). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/405648/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.