ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.1268G>A (p.Arg423His)

gnomAD frequency: 0.00001  dbSNP: rs199576140
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000552624 SCV000646473 uncertain significance Colorectal cancer, susceptibility to, 10 2024-07-22 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 423 of the POLD1 protein (p.Arg423His). This variant is present in population databases (rs199576140, gnomAD 0.003%). 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: 469189). 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.
Ambry Genetics RCV000563416 SCV000671046 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-30 criteria provided, single submitter clinical testing The p.R423H variant (also known as c.1268G>A), located in coding exon 10 of the POLD1 gene, results from a G to A substitution at nucleotide position 1268. The arginine at codon 423 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported as a somatic alteration in a colorectal tumor with microsatellite instability (Shinbrot E et al. Genome Res., 2014 Nov;24:1740-50). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Sema4, Sema4 RCV000563416 SCV002534575 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-04 criteria provided, single submitter curation
GeneDx RCV002293453 SCV002586672 uncertain significance not provided 2022-10-18 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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: 22895193, 20951805, 25228659)
Baylor Genetics RCV000552624 SCV004203434 uncertain significance Colorectal cancer, susceptibility to, 10 2023-12-14 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV004596246 SCV005089727 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing

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