ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6628A>C (p.Lys2210Gln)

gnomAD frequency: 0.00001  dbSNP: rs1284697545
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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 RCV001565181 SCV000772681 uncertain significance not provided 2024-07-16 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2210 of the POLE protein (p.Lys2210Gln). This variant is not present in population databases (gnomAD no frequency). 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: 540727). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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 RCV001565181 SCV001788478 uncertain significance not provided 2020-12-18 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); 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
Fulgent Genetics, Fulgent Genetics RCV002493042 SCV002787559 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 2022-03-02 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004544895 SCV004764366 uncertain significance POLE-related disorder 2023-12-11 no assertion criteria provided clinical testing The POLE c.6628A>C variant is predicted to result in the amino acid substitution p.Lys2210Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is classified as a variant of uncertain significance by outside laboratories in the ClinVar database (https://preview.ncbi.nlm.nih.gov/clinvar/variation/540727/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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