Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000568584 | SCV000674378 | uncertain significance | Hereditary cancer-predisposing syndrome | 2017-04-18 | criteria provided, single submitter | clinical testing | The c.5811G>A variant (also known as p.L1937L), located in coding exon 42 of the POLE gene, results from a G to A substitution at nucleotide position 5811. This nucleotide substitution does not change the at codon 1937. However, this change occurs in the last base pair of coding exon 42, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. 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 |
RCV003539974 | SCV000944055 | uncertain significance | not provided | 2024-06-17 | criteria provided, single submitter | clinical testing | This sequence change affects codon 1937 of the POLE mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the POLE protein. This variant also falls at the last nucleotide of exon 42, which is part of the consensus splice site for this exon. This variant is present in population databases (rs368174082, gnomAD 0.007%). 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: 486124). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with inconclusive levels of altered splicing (Invitae). 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. |
| Gene |
RCV003539974 | SCV005414554 | uncertain significance | not provided | 2024-05-22 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge |