ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.1270C>G (p.Leu424Val) (rs483352909)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000033144 SCV000543910 pathogenic Colorectal cancer, susceptibility to, 12 2019-06-08 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 424 of the POLE protein (p.Leu424Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with colorectal adenomas and carcinomas, being the result of a de novo event in two patients and segregating with disease in at least 4 families (PMID: 23263490, 24501277, 25370038, 25529843, 27683556). ClinVar contains an entry for this variant (Variation ID: 40046). This missense change is located within the evolutionarily conserved exonuclease domain of the POLE protein (PMID: 23447401). Disruption of this amino acid residue is thought to affect the proof-reading function of the polymerase, possibly leading to a hypermutation phenotype (PMID: 23263490, 12424237, 16699561). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000484685 SCV000568806 pathogenic not provided 2017-02-03 criteria provided, single submitter clinical testing This pathogenic variant is denoted POLE c.1270C>G at the cDNA level, p.Leu424Val (L424V) at the protein level, and results in the change of a Leucine to a Valine (CTC>GTC). POLE Leu424Val has been observed in multiple individuals with either an attenuated polyposis phenotype or a history of early onset colorectal cancer, with de novo occurrence reported in two individuals (Palles 2013, Elsayed 2014, Chubb 2015). Additionally, Spier et al. (2014) found this variant to segregate with polyposis and/or colorectal cancer diagnoses in three families. While functional assays have not specifically interrogated POLE Leu424Val, the equivalent residue has been found to have an important role in exonuclease activity in both bacteriophage and yeast systems (Hogg 2004, Murphy 2006). POLE Leu424Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. POLE Leu424Val occurs at a position that is conserved across species and is located in the Exo IV motif of the Exonuclease Domain (Preston 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000570294 SCV000671525 pathogenic Hereditary cancer-predisposing syndrome 2017-08-17 criteria provided, single submitter clinical testing Strong segregation with disease (lod >3 = >10 meioses);Significant disease association in appropriately sized case-control study(ies);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family;Other data supporting pathogenic classification;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Deficient protein function in appropriate functional assay(s)
Fulgent Genetics,Fulgent Genetics RCV000762892 SCV000893282 pathogenic Colorectal cancer, susceptibility to, 12; Facial dysmorphism, immunodeficiency, livedo, and short stature 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000033144 SCV000056926 risk factor Colorectal cancer, susceptibility to, 12 2015-08-01 no assertion criteria provided literature only

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