ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1359+5G>A

dbSNP: rs761564635
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000759264 SCV000820348 pathogenic not provided 2024-08-10 criteria provided, single submitter clinical testing This sequence change falls in intron 13 of the POLE gene. It does not directly change the encoded amino acid sequence of the POLE protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. 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 POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 571386). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (Invitae). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759264 SCV000888495 uncertain significance not provided 2024-05-23 criteria provided, single submitter clinical testing The POLE c.1359+5G>A variant has not been reported in individuals with POLE-related conditions in the published literature. However, this variant has been reported to interfere with normal POLE mRNA splicing (Invitae, personal communication regarding ClinVar ID 571386). The frequency of this variant in the general population, 0.000004 (1/248456 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on POLE mRNA splicing yielded inconclusive findings. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx RCV000759264 SCV005080564 uncertain significance not provided 2024-05-24 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Fulgent Genetics, Fulgent Genetics RCV005010689 SCV005633761 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency 2024-02-23 criteria provided, single submitter clinical testing

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