ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1123C>T (p.Arg375Trp)

dbSNP: rs556789278
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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 RCV004692106 SCV000817476 uncertain significance not provided 2025-01-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 375 of the POLE protein (p.Arg375Trp). This variant is present in population databases (rs556789278, gnomAD 0.007%). This missense change has been observed in individual(s) with gastric cancer (PMID: 36627197). ClinVar contains an entry for this variant (Variation ID: 569231). 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 expected to disrupt POLE protein function with a positive 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.
Ambry Genetics RCV002440442 SCV002751403 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-17 criteria provided, single submitter clinical testing The p.R375W variant (also known as c.1123C>T), located in coding exon 12 of the POLE gene, results from a C to T substitution at nucleotide position 1123. The arginine at codon 375 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV000689809 SCV004203547 uncertain significance Colorectal cancer, susceptibility to, 12 2024-02-16 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV004692106 SCV005192071 uncertain significance not provided criteria provided, single submitter not provided

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