ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.2933G>A (p.Arg978His)

gnomAD frequency: 0.00001  dbSNP: rs371628260
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000230108 SCV000287601 uncertain significance Colorectal cancer, susceptibility to, 10 2024-01-16 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 978 of the POLD1 protein (p.Arg978His). 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: 239319). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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 RCV001537270 SCV001754132 uncertain significance not provided 2020-03-05 criteria provided, single submitter clinical testing 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
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000230108 SCV001775534 uncertain significance Colorectal cancer, susceptibility to, 10 2021-08-05 criteria provided, single submitter clinical testing The POLD1 c.2933G>A (p.Arg978His) missense change has a maximum subpopulation frequency of 0.0043% in gnomAD v2.1.1, however this data may be unreliable due to poor data quality at this location (https://gnomad.broadinstitute.org/variant/19-50919765-G-A). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in a tumor with low tumor mutational burden (PMID: 29056344). To our knowledge, this variant has not been reported in the literature in individuals with POLD1-related disease. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: no criteria met.
Ambry Genetics RCV002436022 SCV002752427 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-13 criteria provided, single submitter clinical testing The p.R978H variant (also known as c.2933G>A), located in coding exon 22 of the POLD1 gene, results from a G to A substitution at nucleotide position 2933. The arginine at codon 978 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.

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