Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000508279 | SCV000602050 | uncertain significance | not specified | 2017-03-25 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000570392 | SCV000671668 | uncertain significance | Hereditary cancer-predisposing syndrome | 2017-02-27 | criteria provided, single submitter | clinical testing | The c.4551+2_4551+3delTG intronic alteration results from a deletion of two nucleotides at nucleotide positions c.4551+2 and 4551+3 of the POLE gene. This nucleotide region is well 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 of 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. |
| Labcorp Genetics |
RCV003539907 | SCV000772586 | pathogenic | not provided | 2025-01-23 | criteria provided, single submitter | clinical testing | This sequence change affects a splice site in intron 35 of the POLE gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (no rsID available, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with colorectal cancer (PMID: 28975465). ClinVar contains an entry for this variant (Variation ID: 439274). Studies have shown that disruption of this splice site results in skipping of exon 35, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic. |
| Prevention |
RCV004535635 | SCV004112985 | likely pathogenic | POLE-related disorder | 2023-03-13 | criteria provided, single submitter | clinical testing | The POLE c.4551+2_4551+3delTG variant is predicted to result in a deletion affecting a canonical splice site. This variant has been reported in at least one individual with breast cancer (Table S4, Siraj et al. 2017. PubMed ID: 28975465). The c.4551+2_4551+3del variant is predicted to disrupt the consensus GT donor site in POLE. This variant is reported in 1 of ~31,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/12-133219806-TCA-T). This variant has conflicting interpretations of likely pathogenic and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/439274/). Pathogenic variants in POLE leading to loss of POLE protein function have been reported in individuals with autosomal recessive intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (IMAGe-I) syndrome (Pachlopnik Schmid et al. 2012. PubMed ID: 23230001; Thiffault et al. 2015. PubMed ID: 25948378; Long et al. 2018. PubMed ID: 30503519; Nakano et al. 2022. PubMed ID: 35534205). 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. |