Submissions for variant NM_006231.4(POLE):c.1021-26_1045delinsGTTCTACACC

dbSNP: rs1555229232

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478654	SCV000569792	uncertain significance	not provided	2018-02-12	criteria provided, single submitter	clinical testing	This combined deletion and insertion is denoted POLE c.1021-26_1045del51ins10 and consists of a deletion of 51 nucleotides and the addition of 10 nucleotides at the intron/exon boundary of exon 11. The normal sequence, with the bases that are deleted and duplicated in brackets, is agac[del51][insgttctacacc]AACA where the capital letters are exonic and the lower case are intronic. This variant has not, to our knowledge, been published in the literature. This variant removes the canonical splice acceptor site as well as the first 25 nucleotides of exon 11 and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. However, while missense variants located within the exonuclease domain of the POLE gene have been recognized as an underlying cause of Polymerase Proofreading-Associated Polyposis (PPAP), an autosomal dominant condition associated with polyposis and an increased risk for colon cancer (Palles 2013, Spier 2015), there are no data to support that loss-of-function variants, such as this one, confer the same cancer risks. Smith et al. (2013) identified a POLE frameshift variant in a 26 year old with a history of colorectal cancer, but no information about family history was provided. Based on current evidence, we consider this variant to be of uncertain significance with respect to cancer. A recessive disease associated with POLE has been reported in the literature. In one large consanguineous family, 14 affected relatives with a syndrome called FILS (facial dysmorphism, immunodeficiency, livedo, and short stature) were all found to be homozygous for POLE c.4444+3A>G, a splice variant which results in a small proportion (~10%) of normal POLE transcript (Pachlopnik Schmid 2012). In addition, an unrelated individual with a suspected chromosome instability syndrome was also found to be homozygous for POLE c.4444+3A>G (Thiffault 2015). We cannot assess whether the variant identified in the current patient would cause the same recessive disease. Individuals and family members of reproductive age may choose to consider assessment of potential reproductive risks.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000478654	SCV000653024	likely pathogenic	not provided	2023-10-26	criteria provided, single submitter	clinical testing	This variant results in the deletion of part of exon 11 (c.1021-26_1045delinsGTTCTACACC) of the POLE gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in POLE are known to be pathogenic (PMID: 23230001, 25948378, 30503519). This variant is not present in population databases (gnomAD no frequency). 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: 420813). 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.
Ambry Genetics	RCV002402400	SCV002670538	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-29	criteria provided, single submitter	clinical testing	The c.1021-26_1045del51insGTTCTACACC variant spans the canonical acceptor site of coding exon 11 in the POLE gene. This variant results from a deletion of 51 nucleotides and insertion of GTTCTACACC nucleotides at positions c.1021-26 to c.1045. The canonical acceptor site is highly conserved in available vertebrate species. Using the BDGP splice site prediction tool, the native acceptor site could not be reliably predicted. However, the ESEfinder splice site prediction tool predicts the creation of a new alternate splice acceptor site that would result in an in-frame transcript; 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.