Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV001025382 | SCV001187560 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-04-29 | criteria provided, single submitter | clinical testing | The c.6538delG variant, located in coding exon 47 of the POLE gene, results from a deletion of one nucleotide at nucleotide position 6538, causing a translational frameshift with a predicted alternate stop codon (p.A2180Rfs*22). This alteration is expected to result in loss of function by premature protein truncation or 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. |
Invitae | RCV003656167 | SCV001376225 | pathogenic | not provided | 2023-07-07 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Ala2180Argfs*22) in the POLE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLE are known to be pathogenic (PMID: 23230001, 25948378, 30503519). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 826469). For these reasons, this variant has been classified as Pathogenic. |
Prevention |
RCV003396615 | SCV004118709 | likely pathogenic | POLE-related condition | 2023-10-04 | criteria provided, single submitter | clinical testing | The POLE c.6538delG variant is predicted to result in a frameshift and premature protein termination (p.Ala2180Argfs*22). To our knowledge, this variant has not been reported in the literature. This variant is reported in 2 of ~248,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/12-133202349-GC-G). It has conflicting interpretations of pathogenic and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/826469/). Frameshift variants in POLE are expected to be pathogenic for autosomal recessive IMAGe-I syndrome. This variant is interpreted as likely pathogenic for autosomal recessive IMAGe-I syndrome and as a variant of uncertain significance for autosomal dominant POLE-associated disorders. |