ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.6539C>T (p.Ala2180Val) (rs552452448)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236907 SCV000293650 uncertain significance not specified 2017-05-18 criteria provided, single submitter clinical testing This variant is denoted POLE c.6539C>T at the cDNA level, p.Ala2180Val (A2180V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Ala2180Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. POLE Ala2180Val occurs at a position that is not conserved and is not located in a known functional domain (Preston 2010). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether POLE Ala2180Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV001082460 SCV000653450 likely benign Colorectal cancer, susceptibility to, 12 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586269 SCV000698686 benign not provided 2017-07-28 criteria provided, single submitter clinical testing Variant summary: The POLE c.6539C>T (p.Ala2180Val) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 26/120212 control chromosomes at a frequency of 0.0002163, which is approximately 15 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142). The variant is also identified in gnomAD dataset at a frequency 0.00019 (51/273776 chrs tested), predominantly in individuals of South Asian descent (0.0014; 43/30768 chrs tested), suggesting that this change is likely to be a functional ethnic polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as Benign.

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