ClinVar Miner

Submissions for variant NM_001256849.1(POLD1):c.1552C>A (p.Leu518Met) (rs149043082)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566097 SCV000671009 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000657132 SCV000570134 uncertain significance not provided 2018-07-27 criteria provided, single submitter clinical testing This variant is denoted POLD1 c.1552C>A at the cDNA level, p.Leu518Met (L518M) at the protein level, and results in the change of a Leucine to a Methionine (CTG>ATG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. POLD1 Leu518Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). However, it was reported in at least one control who denied a personal or family history of colorectal cancer (Arora 2015). This variant is located in the exoIII motif of the exonuclease domain (Preston 2010). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether POLD1 Leu518Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000528834 SCV000646491 uncertain significance Colorectal cancer 10 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces leucine with methionine at codon 518 of the POLD1 protein (p.Leu518Met). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and methionine. This variant is present in population databases (rs149043082, ExAC 0.003%). This variant has not been reported in the literature in individuals with a POLD1-related disease. ClinVar contains an entry for this variant (Variation ID: 421052). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on POLD1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000483221 SCV000731391 uncertain significance not specified 2017-02-27 criteria provided, single submitter clinical testing The p.Leu518Met variant in POLD1 has not been previously reported in individuals with colorectal cancer, but has been identified in 2/66222 of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs149043082). Computational prediction tools and conservation analysis sugg est that the p.Leu518Met variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical s ignificance of the p.Leu518Met variant is uncertain.

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