ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.2317G>A (p.Ala773Thr)

gnomAD frequency: 0.00008  dbSNP: rs753865441
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232792 SCV000287565 uncertain significance Colorectal cancer, susceptibility to, 10 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 773 of the POLD1 protein (p.Ala773Thr). This variant is present in population databases (rs753865441, gnomAD 0.01%). 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: 239283). 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 RCV000482798 SCV000569006 likely benign not provided 2021-05-03 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; Observed in an individual undergoing multi-gene hereditary cancer panel testing based on personal and/or family history of cancer (Cabanillas 2017); This variant is associated with the following publications: (PMID: 28717660)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001251336 SCV001426899 likely benign not specified 2020-07-02 criteria provided, single submitter clinical testing Variant summary: POLD1 c.2317G>A (p.Ala773Thr) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain (IPR006134) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 249614 control chromosomes. The observed variant frequency is approximately 2.8 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 benign. To our knowledge, no occurrence of c.2317G>A in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two 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 RCV000482798 SCV001469864 uncertain significance not provided 2019-12-31 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001251336 SCV004027015 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing

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