ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.665C>T (p.Pro222Leu)

gnomAD frequency: 0.00002  dbSNP: rs368940099
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000470943 SCV000547571 uncertain significance Colorectal cancer, susceptibility to, 10 2024-01-19 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 222 of the POLD1 protein (p.Pro222Leu). This variant is present in population databases (rs368940099, 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: 408023). 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 RCV001552706 SCV001773444 uncertain significance not provided 2023-09-15 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25957691)
Ambry Genetics RCV002365630 SCV002663272 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-23 criteria provided, single submitter clinical testing The p.P222L variant (also known as c.665C>T), located in coding exon 5 of the POLD1 gene, results from a C to T substitution at nucleotide position 665. The proline at codon 222 is replaced by leucine, an amino acid with 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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