ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5553-12C>G

gnomAD frequency: 0.00006  dbSNP: rs766922669
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236988 SCV000293816 uncertain significance not provided 2024-02-27 criteria provided, single submitter clinical testing In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV000236988 SCV002362719 likely benign not provided 2025-01-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000236988 SCV004565185 uncertain significance not provided 2023-01-06 criteria provided, single submitter clinical testing The POLE c.5553-12C>G variant (rs766922669), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 246317). This variant is found in the general population with an overall allele frequency of 0.004% (10/250,840 alleles) in the Genome Aggregation Database. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site. However, the established disease mechanism in POLE involves missense variants in the exonuclease domain (Palles 2013), and gene-disease association has not been established for variants outside of the exonuclease domain (Seifert 2019). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Palles C et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013 Feb;45(2):136-44. PMID: 23263490. Seifert BA et al. Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework. Genet Med. 2019 Jul;21(7):1507-1516. PMID: 30523343.

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