Submissions for variant NM_006231.4(POLE):c.1020+5_1020+6delinsAA

dbSNP: rs1064795707

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485457	SCV000571769	likely benign	not specified	2016-09-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV001009725	SCV001169825	uncertain significance	Hereditary cancer-predisposing syndrome	2019-01-21	criteria provided, single submitter	clinical testing	The c.1020+5_1020+6delGGinsAA intronic variant, located in intron 10 of the POLE gene, results from an in-frame deletion of two nucleotides and the insertion of two nucleotides at intronic positions +5 and +6 after coding exon 10. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003656118	SCV001224949	uncertain significance	not provided	2024-07-25	criteria provided, single submitter	clinical testing	This sequence change falls in intron 10 of the POLE gene. It does not directly change the encoded amino acid sequence of the POLE protein. It affects a nucleotide within the consensus splice site. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the 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: 422325). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003656118	SCV005625190	uncertain significance	not provided	2023-11-24	criteria provided, single submitter	clinical testing	The POLE c.1020+5_1020+6delinsAA variant has not been reported in individuals with POLE-related conditions in the published literature. The frequency of this variant in the general population, 0.00024 (7/29460 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on POLE mRNA splicing yielded inconclusive findings. Based on the available information, we are unable to determine the clinical significance of this variant.