ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.1270G>T (p.Val424Leu)

dbSNP: rs1315928771
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000571312 SCV000674304 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-31 criteria provided, single submitter clinical testing The p.V424L variant (also known as c.1270G>T), located in coding exon 10 of the POLD1 gene, results from a G to T substitution at nucleotide position 1270. The valine at codon 424 is replaced by leucine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 80000 alleles tested) in our clinical cohort. This amino acid position is well 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.
Invitae RCV001045280 SCV001209120 uncertain significance Colorectal cancer, susceptibility to, 10 2019-03-13 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 486079). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 424 of the POLD1 protein (p.Val424Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine.

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