ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.426C>G (p.His142Gln)

gnomAD frequency: 0.00004  dbSNP: rs201187429
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000547260 SCV000646664 uncertain significance Colorectal cancer, susceptibility to, 10 2024-01-30 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 142 of the POLD1 protein (p.His142Gln). This variant is present in population databases (rs201187429, gnomAD 0.008%). 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: 469351). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
MGZ Medical Genetics Center RCV000547260 SCV002578975 uncertain significance Colorectal cancer, susceptibility to, 10 2022-04-25 criteria provided, single submitter clinical testing
GeneDx RCV003148780 SCV003837287 uncertain significance not provided 2023-03-03 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31034466)
Ambry Genetics RCV003159860 SCV003909124 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-19 criteria provided, single submitter clinical testing The p.H142Q variant (also known as c.426C>G), located in coding exon 3 of the POLD1 gene, results from a C to G substitution at nucleotide position 426. The histidine at codon 142 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.

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