ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.2045G>A (p.Arg682Gln)

gnomAD frequency: 0.00002  dbSNP: rs773665739
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000468664 SCV000547599 uncertain significance Colorectal cancer, susceptibility to, 10 2024-01-06 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 682 of the POLD1 protein (p.Arg682Gln). This variant is present in population databases (rs773665739, gnomAD 0.009%). 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: 408047). 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 RCV001770330 SCV002001897 uncertain significance not provided 2020-01-27 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002418376 SCV002726473 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-06 criteria provided, single submitter clinical testing The p.R682Q variant (also known as c.2045G>A), located in coding exon 16 of the POLD1 gene, results from a G to A substitution at nucleotide position 2045. The arginine at codon 682 is replaced by glutamine, an amino acid with highly similar 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.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355494 SCV001550399 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The POLD1 p.Arg682Gln variant was not identified in the literature. The variant was identified in dbSNP (rs773665739) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 4 of 249,760 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 3 of 34,564 chromosomes (freq: 0.00008) and European in 1 of 112,378 chromosomes (freq: 0.000009), while it was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, Other or South Asian populations. The p.Arg682 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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