ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2599G>A (p.Val867Ile)

gnomAD frequency: 0.00004  dbSNP: rs374200895
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000657131 SCV000289300 uncertain significance not provided 2025-01-26 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 867 of the POLE protein (p.Val867Ile). This variant is present in population databases (rs374200895, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 35534704). ClinVar contains an entry for this variant (Variation ID: 240436). 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 RCV000657131 SCV000569879 uncertain significance not provided 2024-11-12 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in an individual with a personal and family history of breast and other cancers (PMID: 35534704); This variant is associated with the following publications: (PMID: 24651015, 20951805, 35534704)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657131 SCV000602008 uncertain significance not provided 2019-06-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563337 SCV000671335 likely benign Hereditary cancer-predisposing syndrome 2024-12-05 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000657131 SCV002009592 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005003577 SCV005633736 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 2024-01-03 criteria provided, single submitter clinical testing

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