ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.2039C>T (p.Pro680Leu)

gnomAD frequency: 0.00003  dbSNP: rs765557862
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464867 SCV000547613 uncertain significance Colorectal cancer, susceptibility to, 10 2023-01-24 criteria provided, single submitter clinical testing 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. 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 expected to disrupt POLD1 protein function. ClinVar contains an entry for this variant (Variation ID: 408061). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is present in population databases (rs765557862, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 680 of the POLD1 protein (p.Pro680Leu).
GeneDx RCV001799661 SCV002043950 uncertain significance not provided 2021-06-24 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Chen 2020); This variant is associated with the following publications: (PMID: 27535533, 32091409)
Ambry Genetics RCV003168792 SCV003912727 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-23 criteria provided, single submitter clinical testing The p.P680L variant (also known as c.2039C>T), located in coding exon 16 of the POLD1 gene, results from a C to T substitution at nucleotide position 2039. The proline at codon 680 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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