ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.1646G>A (p.Arg549His)

gnomAD frequency: 0.00001  dbSNP: rs201038430
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234700 SCV000287528 uncertain significance Colorectal cancer, susceptibility to, 10 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 549 of the POLD1 protein (p.Arg549His). This variant is present in population databases (rs201038430, gnomAD 0.006%). 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: 239247). 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 with a positive 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 RCV002288921 SCV002578874 uncertain significance not provided 2022-10-07 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with colorectal cancer (Buchanan et al., 2017); This variant is associated with the following publications: (PMID: 29120461, 35620275, 32041611)
PreventionGenetics, part of Exact Sciences RCV003417814 SCV004114984 uncertain significance POLD1-related condition 2023-01-05 criteria provided, single submitter clinical testing The POLD1 c.1646G>A variant is predicted to result in the amino acid substitution p.Arg549His. This variant has been reported in one individual with colorectal cancer (Table S3, Buchanan et al. 2018. PubMed ID: 29120461) and in at least one individual with dyslipidemia (Dron et al. 2020. PubMed ID: 32041611). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-50910391-G-A). This variant has been classified as a variant of uncertain significance in Clinvar by two different submitters (Clinvar ID: 239247). This variant is not located in the exonuclease domain of the POLD1 protein. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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