ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.229C>T (p.Arg77Cys)

gnomAD frequency: 0.00001  dbSNP: rs1060500889
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003539898 SCV000544223 uncertain significance not provided 2024-11-13 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 77 of the POLE protein (p.Arg77Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with early-onset colorectal cancer (PMID: 28195393). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 405896). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLE protein function. 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 RCV003539898 SCV005079727 uncertain significance not provided 2024-04-17 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed to segregate with disease in at least one family with colorectal cancer and polyps (PMID: 28195393); This variant is associated with the following publications: (PMID: 25931171, 25991819, 28195393)
Fulgent Genetics, Fulgent Genetics RCV005010349 SCV005633783 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 2024-06-20 criteria provided, single submitter clinical testing

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