ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.2794G>C (p.Gly932Arg)

gnomAD frequency: 0.00001  dbSNP: rs761355038
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467511 SCV000547645 uncertain significance Colorectal cancer, susceptibility to, 10 2023-12-13 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 932 of the POLD1 protein (p.Gly932Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 408092). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
GeneDx RCV001584153 SCV001811973 uncertain significance not provided 2023-10-04 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000467511 SCV002012388 uncertain significance Colorectal cancer, susceptibility to, 10 2021-09-09 criteria provided, single submitter clinical testing The POLD1 c.2794G>C (p.Gly932Arg) missense change has a maximum subpopulation frequency of 0.0028% in gnomAD v2.1.1, however this data may be unreliable due to poor data quality at this location (https://gnomad.broadinstitute.org/variant/19-50919057-G-C). Five of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in two tumors with a low tumor mutational burden (PMID: 29056344). To our knowledge, this variant has not been reported in the literature in individuals with POLD1-related disease. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3.
Sema4, Sema4 RCV002255391 SCV002534651 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-12 criteria provided, single submitter curation
Ambry Genetics RCV002255391 SCV002747358 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-25 criteria provided, single submitter clinical testing The p.G932R variant (also known as c.2794G>C), located in coding exon 21 of the POLD1 gene, results from a G to C substitution at nucleotide position 2794. The glycine at codon 932 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. 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.

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