Submissions for variant NM_006231.4(POLE):c.6016G>T (p.Ala2006Ser)

dbSNP: rs1328375671

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000603210	SCV000712720	uncertain significance	not specified	2016-12-08	criteria provided, single submitter	clinical testing	The p.Ala2006Ser variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 1/3514 of Finnish chromosome s by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical signif icance of the p.Ala2006Ser variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001584421	SCV000772664	uncertain significance	not provided	2024-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2006 of the POLE protein (p.Ala2006Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 505484). 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	RCV001584421	SCV001820551	uncertain significance	not provided	2019-10-11	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002358672	SCV002656614	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-29	criteria provided, single submitter	clinical testing	The p.A2006S variant (also known as c.6016G>T), located in coding exon 44 of the POLE gene, results from a G to T substitution at nucleotide position 6016. The alanine at codon 2006 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. 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.