ClinVar Miner

Submissions for variant NM_001256849.1(POLD1):c.1517G>A (p.Arg506His) (rs140379348)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000574478 SCV000671128 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Invitae RCV000227201 SCV000287523 uncertain significance Colorectal cancer 10 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 506 of the POLD1 protein (p.Arg506His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs140379348, ExAC 0.002%). This variant has not been reported in the literature in individuals with POLD1-related disease. ClinVar contains an entry for this variant (Variation ID: 239242). In an experimental yeast model system a slight reduction in DNA proofreading activity of the POLD1 protein was observed for cells containing this sequence change. In this same study no effect on sensitivity to DNA-damaging agents was detected (PMID: 19966286). The clinical significance of these results is unknown at this time. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000610546 SCV000731336 uncertain significance not specified 2016-12-28 criteria provided, single submitter clinical testing The p.Arg506His variant in POLD1 has not been previously reported in individuals with colorectal cancer, but has been identified in 1/64598 of European chromoso mes by the Exome Aggregation Consortium (ExAC,; d bSNP rs140379348). In vitro functional studies provide some evidence that the p. Arg506His variant may impact protein function (Daee 2010). However, these types of assays may not accurately represent biological function. Computational predic tion tools and conservation analysis do not provide strong support for or agains t an impact to the protein. In summary, the clinical significance of the p.Arg50 6His variant is uncertain.

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