ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.3158G>A (p.Arg1053His)

gnomAD frequency: 0.00001  dbSNP: rs980793204
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000809272 SCV000949418 uncertain significance Colorectal cancer, susceptibility to, 10 2024-01-05 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 1053 of the POLD1 protein (p.Arg1053His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 653488). 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.
Ambry Genetics RCV003307497 SCV003997533 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-14 criteria provided, single submitter clinical testing The p.R1053H variant (also known as c.3158G>A), located in coding exon 25 of the POLD1 gene, results from a G to A substitution at nucleotide position 3158. The arginine at codon 1053 is replaced by histidine, 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV000809272 SCV004015255 uncertain significance Colorectal cancer, susceptibility to, 10 2023-07-07 criteria provided, single submitter clinical testing For the POLD1 variant, the sequence change replaces arginine with histidine at codon 1053 of the POLD1 protein (p.Arg1053His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (ExAC frequency 0.004%). This variant has not been reported in the literature in individuals with POLD1-related disease. In-silico simulator softwares to predict the effect of missense changes on protein structure and function showed (SIFT: deleterious; PolyPhen-2: probably damaging). Therefore, it has been classified as a Variant of Uncertain Significance.

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