ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1064A>G (p.Lys355Arg)

gnomAD frequency: 0.00012  dbSNP: rs141396559
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000485791 SCV000289237 uncertain significance not provided 2025-02-03 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 355 of the POLE protein (p.Lys355Arg). This variant is present in population databases (rs141396559, gnomAD 0.05%). 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: 240374). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE protein function with a negative predictive value of 80%. 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.
GeneDx RCV000485791 SCV000572894 uncertain significance not provided 2024-10-29 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20951805)
Ambry Genetics RCV000575355 SCV000671377 likely benign Hereditary cancer-predisposing syndrome 2024-01-23 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics RCV000763816 SCV000894733 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome 2018-10-31 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV000234726 SCV001434297 uncertain significance Colorectal cancer, susceptibility to, 12 2020-05-05 criteria provided, single submitter clinical testing To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an overall allele frequency of 0.00005 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/), and is more common in populations of African ancestry. This variant is in the exonuclease domain of the protein where other pathogenic sequence variants have been found. In silico analyses indicate that this variant may not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4; PM1
Baylor Genetics RCV000234726 SCV004203528 uncertain significance Colorectal cancer, susceptibility to, 12 2024-03-25 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000234726 SCV005402247 uncertain significance Colorectal cancer, susceptibility to, 12 2024-03-15 criteria provided, single submitter clinical testing The POLE c.1064A>G (p.Lys355Arg) missense change has a maximum subpopulation frequency of 0.05% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but this prediction has not been confirmed by functional studies. This variant has not been reported in the literature in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV005008188 SCV005633764 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 2024-02-18 criteria provided, single submitter clinical testing

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