ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.1420G>A (p.Val474Ile) (rs980578884)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000417197 SCV000786198 uncertain significance Colorectal cancer, susceptibility to, 12 2018-03-16 criteria provided, single submitter clinical testing
Invitae RCV000417197 SCV000943380 uncertain significance Colorectal cancer, susceptibility to, 12 2020-10-18 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 474 of the POLE protein (p.Val474Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with colorectal cancer (PMID: 28423643). ClinVar contains an entry for this variant (Variation ID: 235886). This variant has been reported to affect POLE protein function (PMID: 28423643). 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.
Ambry Genetics RCV001011505 SCV001171832 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-08 criteria provided, single submitter clinical testing The p.V474I variant (also known as c.1420G>A), located in coding exon 14 of the POLE gene, results from a G to A substitution at nucleotide position 1420. The valine at codon 474 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in an early-onset colorectal cancer patient from a Amsterdam I family without alterations in the mismatch repair system (Esteban-Jurado C et al. Oncotarget, 2017 Apr;8:26732-26743). Further, a functional analysis by Esteban-Jurado et al. using a yeast based model showed this alteration resulted in an increased mutation rate due to faulty proofreading activity as compared to wild type, but was still milder than the previously reported mutation p.Leu424Val. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genetic Predisposition to Colorectal Cancer Group,Institut d’Investigacions Biomediques August Pi i Sunyer RCV000417197 SCV000268710 pathogenic Colorectal cancer, susceptibility to, 12 2016-05-25 no assertion criteria provided research The POLE c.1420G>A (p.Val474Ile) variant was not present in any of the accessed human genetic variation databases including a Spanish repository (dbSNP, 1000Genomes, Exome Variant Server, Exome Aggregation Consortium and CIBERER Spanish variant server). The affected amino acid is conserved in 100 vertebrates as well as in D. melanogaster, C. elegans and yeast, and it is very close to the C terminus end of the exonuclease domain (3 amino acids away). Analysis of the POLE structure showed that the variant may not affect DNA binding directly but it could have an indirect effect on the helical packing of the exonuclease and N-terminal domains, which could distort the physiological conformation needed for a correct polymerase activity. Also, bioinformatics tools (PolyPhen and CADD) predicted a deleterious effect for this amino acid change and protein stability predictions were also in favor of a damaging effect. Functional studies on S. pombe concluded that the mutation rate of this variant was 31 times higher when compared to the wild-type strain (P-value <0.005) but milder than the previously reported p.Leu424Val.

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