ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.2545C>T (p.Arg849Cys)

gnomAD frequency: 0.00003  dbSNP: rs759987234
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000704716 SCV000833675 uncertain significance Colorectal cancer, susceptibility to, 10 2025-01-26 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 849 of the POLD1 protein (p.Arg849Cys). This variant is present in population databases (rs759987234, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 581013). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLD1 protein function with a negative predictive value of 80%. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759949 SCV000889667 uncertain significance not provided 2018-05-19 criteria provided, single submitter clinical testing
GeneDx RCV000759949 SCV001782741 uncertain significance not provided 2025-01-10 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29056344, 35620275)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002268264 SCV002551963 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV004944128 SCV005470085 benign Hereditary cancer-predisposing syndrome 2024-08-20 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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