ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.577A>G (p.Ser193Gly)

gnomAD frequency: 0.00001  dbSNP: rs760588718
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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 RCV000487364 SCV000544032 uncertain significance not provided 2025-01-28 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 193 of the POLE protein (p.Ser193Gly). This variant is present in population databases (rs760588718, gnomAD 0.0009%). 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: 405716). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 RCV000487364 SCV000572654 uncertain significance not provided 2023-07-30 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in one unaffected control and in no cases in a study of ovarian cancer patients (Song et al., 2020); This variant is associated with the following publications: (PMID: 32546565)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000464343 SCV001737477 uncertain significance Colorectal cancer, susceptibility to, 12 2021-05-27 criteria provided, single submitter clinical testing The POLE c.577A>G (p.Ser193Gly) missense change has a maximum subpopulation frequency of 0.00089% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/12-133256084-T-C?dataset=gnomad_r2_1). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been identified in a tumor with low tumor mutational burden (internal data). To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP4.
Ambry Genetics RCV003168751 SCV003895839 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-19 criteria provided, single submitter clinical testing The p.S193G variant (also known as c.577A>G), located in coding exon 6 of the POLE gene, results from an A to G substitution at nucleotide position 577. The serine at codon 193 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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