ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.1322C>T (p.Thr441Met)

gnomAD frequency: 0.00005  dbSNP: rs376711125
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226871 SCV000287511 uncertain significance Colorectal cancer, susceptibility to, 10 2024-01-30 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 441 of the POLD1 protein (p.Thr441Met). This variant is present in population databases (rs376711125, gnomAD 0.02%). 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: 239230). 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 RCV000480965 SCV000569283 uncertain significance not provided 2023-07-11 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 a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 20951805, 27071721, 24265153, 25228659)
Ambry Genetics RCV000575300 SCV000670968 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-09 criteria provided, single submitter clinical testing The p.T441M variant (also known as c.1322C>T), located in coding exon 10 of the POLD1 gene, results from a C to T substitution at nucleotide position 1322. The threonine at codon 441 is replaced by methionine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. 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.
Fulgent Genetics, Fulgent Genetics RCV000764220 SCV000895223 uncertain significance Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000480965 SCV001152023 likely benign not provided 2023-01-01 criteria provided, single submitter clinical testing POLD1: BP4
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002267982 SCV002551911 uncertain significance not specified 2024-02-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480965 SCV004219056 uncertain significance not provided 2023-05-30 criteria provided, single submitter clinical testing To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00023 (8/35422 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
True Health Diagnostics RCV000575300 SCV000788127 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-01 no assertion criteria provided clinical testing

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