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 2019-12-03 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 2019-05-02 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
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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