ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5492T>C (p.Leu1831Pro)

gnomAD frequency: 0.00001  dbSNP: rs781674901
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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 RCV003539949 SCV000653369 uncertain significance not provided 2024-11-04 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1831 of the POLE protein (p.Leu1831Pro). This variant is present in population databases (rs781674901, gnomAD 0.004%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 29987844). ClinVar contains an entry for this variant (Variation ID: 473735). 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 RCV003539949 SCV005325561 uncertain significance not provided 2024-01-03 criteria provided, single submitter clinical testing Observed in an individual with early-onset colorectal cancer with tumors displaying microsatellite instability and loss of MSH2 and MSH6 proteins on immunohistochemistry testing, without an identifiable variant in a mismatch repair gene (PMID: 29987844); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29987844)
Ambry Genetics RCV004944004 SCV005478856 uncertain significance Hereditary cancer-predisposing syndrome 2024-10-17 criteria provided, single submitter clinical testing The p.L1831P variant (also known as c.5492T>C), located in coding exon 40 of the POLE gene, results from a T to C substitution at nucleotide position 5492. The leucine at codon 1831 is replaced by proline, an amino acid with similar properties. This alteration was identified in an individual with clinically suspected Lynch syndrome (Kayser K et al. Int J Cancer, 2018 Dec;143:2800-2813). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics RCV005010518 SCV005633682 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 2024-05-14 criteria provided, single submitter clinical testing

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