ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.2969G>A (p.Arg990His)

gnomAD frequency: 0.00001  dbSNP: rs771789997
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000645792 SCV000767547 uncertain significance Colorectal cancer, susceptibility to, 10 2023-09-14 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 990 of the POLD1 protein (p.Arg990His). 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: 537051). 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. 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 RCV002440316 SCV002751572 uncertain significance Hereditary cancer-predisposing syndrome 2021-06-30 criteria provided, single submitter clinical testing The p.R990H variant (also known as c.2969G>A), located in coding exon 23 of the POLD1 gene, results from a G to A substitution at nucleotide position 2969. The arginine at codon 990 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.
PreventionGenetics, part of Exact Sciences RCV003403491 SCV004103995 uncertain significance POLD1-related condition 2023-10-09 criteria provided, single submitter clinical testing The POLD1 c.2969G>A variant is predicted to result in the amino acid substitution p.Arg990His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0056% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-50919882-G-A). It is interpreted as uncertain in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/537051/). 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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