ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.2925C>T (p.Gly975=)

gnomAD frequency: 0.00001  dbSNP: rs376743216
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000528402 SCV000646611 uncertain significance Colorectal cancer, susceptibility to, 10 2023-10-28 criteria provided, single submitter clinical testing This sequence change affects codon 975 of the POLD1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the POLD1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 10 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). 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: 469307). Studies have shown that this variant results in the activation of a cryptic splice site in exon 23 (Invitae). 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 RCV000570959 SCV000671076 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-10 criteria provided, single submitter clinical testing The c.2925C>T variant (also known as p.G975G), located in coding exon 22, results from a C to T substitution at nucleotide position 2925 of the POLD1 gene. This nucleotide substitution does not change the amino acid at codon 975. This nucleotide position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV002289764 SCV002578265 uncertain significance not provided 2022-04-07 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge

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