ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.1536C>A (p.Cys512Ter)

dbSNP: rs373380580
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001012082 SCV001172491 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-20 criteria provided, single submitter clinical testing The p.C512* variant (also known as c.1536C>A), located in coding exon 12 of the POLD1 gene, results from a C to A substitution at nucleotide position 1536. This changes the amino acid from a cysteine to a stop codon within coding exon 12. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of POLD1 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001326371 SCV001517400 uncertain significance Colorectal cancer, susceptibility to, 10 2022-07-12 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 819491). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys512*) in the POLD1 gene. Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLD1 protein are associated with an increased risk for colonic adenomatous polyps and colon cancer (PMID: 23263490, 23447401). However, loss-of-function variants that result in an absent or severely disrupted POLD1 protein, and missense variants outside the exonuclease domain, are unlikely to be associated with polyposis or colon cancer.

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