ClinVar Miner

Submissions for variant NM_001256849.1(POLD1):c.2326C>T (p.Arg776Trp) (rs780138978)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000227620 SCV000287566 uncertain significance Colorectal cancer 10 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 776 of the POLD1 protein (p.Arg776Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs780138978, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with POLD1-related disease. ClinVar contains an entry for this variant (Variation ID: 239284). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000657108 SCV000569140 uncertain significance not provided 2018-09-21 criteria provided, single submitter clinical testing This variant is denoted POLD1 c.2326C>T at the cDNA level, p.Arg776Trp (R776W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant was reported in at least one control individual reporting no personal or family history of colorectal cancer (Arora 2015). POLD1 Arg776Trp was observed at an allele frequency of 0.01% (17/125642) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). This variant is located in Polymerase domain (Preston 2010). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether POLD1 Arg776Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000481293 SCV000712546 uncertain significance not specified 2016-11-15 criteria provided, single submitter clinical testing The p.Arg776Trp variant in POLD1 has not been previously reported in individuals with colorectal cancer but has been identified in 1/6594 of Finnish chromosomes by the Exome Aggregation Consortium (ExAC,; dbSN P rs780138978). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg776Trp variant is uncertain.
True Health Diagnostics RCV000664282 SCV000788139 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-14 no assertion criteria provided clinical testing

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