ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.223A>G (p.Ile75Val)

dbSNP: rs940296193
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000473956 SCV000547640 uncertain significance Colorectal cancer, susceptibility to, 10 2024-01-17 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 75 of the POLD1 protein (p.Ile75Val). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 408088). 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.
Fulgent Genetics, Fulgent Genetics RCV000765470 SCV000896761 uncertain significance Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome 2018-10-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV002429503 SCV002726865 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-24 criteria provided, single submitter clinical testing The p.I75V variant (also known as c.223A>G), located in coding exon 2 of the POLD1 gene, results from an A to G substitution at nucleotide position 223. The isoleucine at codon 75 is replaced by valine, 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.
GeneDx RCV002469154 SCV002765565 uncertain significance not provided 2022-12-14 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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