ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.17G>A (p.Arg6Gln)

gnomAD frequency: 0.00006  dbSNP: rs778275831
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER _CC_NCGL, University of Washington RCV000211516 SCV000212213 uncertain significance Colorectal cancer 2015-03-11 criteria provided, single submitter research
Counsyl RCV000411457 SCV000488981 uncertain significance Colorectal cancer, susceptibility to, 10 2016-07-31 criteria provided, single submitter clinical testing
Invitae RCV000411457 SCV000547641 uncertain significance Colorectal cancer, susceptibility to, 10 2024-01-22 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 6 of the POLD1 protein (p.Arg6Gln). This variant is present in population databases (rs778275831, gnomAD 0.009%). This missense change has been observed in individual(s) with unspecified cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 226047). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics RCV000573664 SCV000670979 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-23 criteria provided, single submitter clinical testing The p.R6Q variant (also known as c.17G>A), located in coding exon 1 of the POLD1 gene, results from a G to A substitution at nucleotide position 17. The arginine at codon 6 is replaced by glutamine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6475 samples (12950 alleles) with coverage at this position. This amino acid position is not well conserved on limited sequence alignment. In addition, this alteration is predicted to be benign yet deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.R6Q remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780642 SCV000918075 likely benign not specified 2018-05-18 criteria provided, single submitter clinical testing Variant summary: POLD1 c.17G>A (p.Arg6Gln) results in a conservative amino acid change located in the outside of any known functional domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 79494 control chromosomes, predominantly at a frequency of 0.00025 within the Non-Finnish European subpopulation in the ExAC database. The observed variant frequency within Non-Finnish European control individuals in the ExAC database is approximately 18 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.17G>A in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985925 SCV001134633 uncertain significance not provided 2018-12-13 criteria provided, single submitter clinical testing
GeneDx RCV000985925 SCV001804225 uncertain significance not provided 2023-06-04 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000780642 SCV002761039 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing

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