ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1957G>T (p.Ala653Ser)

gnomAD frequency: 0.00005  dbSNP: rs751451482
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766612 SCV000570293 uncertain significance not provided 2023-02-21 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV000766612 SCV000653100 uncertain significance not provided 2025-01-28 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 653 of the POLE protein (p.Ala653Ser). This variant is present in population databases (rs751451482, gnomAD 0.02%). 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: 421176). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000480178 SCV000731314 uncertain significance not specified 2016-12-08 criteria provided, single submitter clinical testing The p.Ala653Ser variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 2/10378 African chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs751451482). Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, the cl inical significance of the p.Ala635Ser variant is uncertain
Counsyl RCV000550579 SCV000786172 uncertain significance Colorectal cancer, susceptibility to, 12 2018-03-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV003168957 SCV003894047 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-17 criteria provided, single submitter clinical testing The p.A653S variant (also known as c.1957G>T), located in coding exon 18 of the POLE gene, results from a G to T substitution at nucleotide position 1957. The alanine at codon 653 is replaced by serine, 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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