ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.2563C>T (p.Arg855Ter)

gnomAD frequency: 0.00002  dbSNP: rs768048535
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000473508 SCV000547537 uncertain significance Colorectal cancer, susceptibility to, 10 2024-01-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg855*) in the POLD1 gene. Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLD1 protein are associated with PPAP (polymerase proofreading–associated polyposis) (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 PPAP. 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: 407990). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (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 RCV000566422 SCV000676211 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-13 criteria provided, single submitter clinical testing The p.R855* variant (also known as c.2563C>T), located in coding exon 19 of the POLD1 gene, results from a C to T substitution at nucleotide position 2563. This changes the amino acid from an arginine to a stop codon within coding exon 19. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function via haploinsufficiency in 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.
GeneDx RCV000657755 SCV000779507 uncertain significance not provided 2020-09-28 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay, but clinical significance is uncertain; Some missense variants in POLD1 have been recognized as an underlying cause of Polymerase Proofreading-Associated Polyposis (PPAP); however, there are no data at this time to support that loss-of-function variants confer the same cancer risks; Has not been previously published as a germline pathogenic or benign variant to our knowledge; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 29056344)
Fulgent Genetics, Fulgent Genetics RCV000764229 SCV000895232 uncertain significance Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome 2018-10-31 criteria provided, single submitter clinical testing

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