ClinVar Miner

Submissions for variant NM_001256849.1(POLD1):c.17G>A (p.Arg6Gln) (rs778275831)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000573664 SCV000670979 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes)
CSER_CC_NCGL; University of Washington Medical Center RCV000211516 SCV000212213 uncertain significance Colorectal cancer 2015-03-11 criteria provided, single submitter research
Counsyl RCV000411457 SCV000488981 uncertain significance Colorectal cancer 10 2016-07-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000411457 SCV000547641 uncertain significance Colorectal cancer 10 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 6 of the POLD1 protein (p.Arg6Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs778275831, 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: 226047). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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