Submissions for variant NM_006231.4(POLE):c.1020+1G>T

dbSNP: rs1064794748

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478662	SCV000569869	likely pathogenic	not provided	2024-09-12	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20951805)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000478662	SCV000933002	likely pathogenic	not provided	2023-03-11	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 420859). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This sequence change affects a donor splice site in intron 10 of the POLE gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
Ambry Genetics	RCV001009724	SCV001169824	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-09	criteria provided, single submitter	clinical testing	The c.1020+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 10 of the POLE gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, loss of function via haploinsufficiency in POLE has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.