ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2711G>C (p.Gly904Ala)

gnomAD frequency: 0.00001  dbSNP: rs1332965505
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000610774 SCV000731299 uncertain significance not specified 2016-11-17 criteria provided, single submitter clinical testing The p.Gly904Ala variant in POLE has not been previously reported in individuals with colorectal cancer or in large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Gly904Ala variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp RCV003539987 SCV000827475 uncertain significance not provided 2025-01-11 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 904 of the POLE protein (p.Gly904Ala). 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: 517178). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
Ambry Genetics RCV004649229 SCV005154327 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-22 criteria provided, single submitter clinical testing The c.2711G>C (p.G904A) alteration is located in exon 24 (coding exon 24) of the POLE gene. This alteration results from a G to C substitution at nucleotide position 2711, causing the glycine (G) at amino acid position 904 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV005004269 SCV005633734 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 2024-06-19 criteria provided, single submitter clinical testing

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