ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5206G>A (p.Val1736Ile)

gnomAD frequency: 0.00005  dbSNP: rs770181299
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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 RCV003151772 SCV000543979 uncertain significance not provided 2025-01-29 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1736 of the POLE protein (p.Val1736Ile). This variant is present in population databases (rs770181299, gnomAD 0.01%). 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: 405666). 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 RCV003151772 SCV003840721 uncertain significance not provided 2023-07-12 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV004943848 SCV005484513 uncertain significance Hereditary cancer-predisposing syndrome 2024-08-20 criteria provided, single submitter clinical testing The c.5206G>A (p.V1736I) alteration is located in exon 39 (coding exon 39) of the POLE gene. This alteration results from a G to A substitution at nucleotide position 5206, causing the valine (V) at amino acid position 1736 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV005010340 SCV005633686 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 2024-02-05 criteria provided, single submitter clinical testing

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