Submissions for variant NM_006231.4(POLE):c.6539C>T (p.Ala2180Val)

gnomAD frequency: 0.00004  dbSNP: rs552452448

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586269	SCV000293650	uncertain significance	not provided	2020-12-01	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; This variant is associated with the following publications: (PMID: 22980975, 28427513)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000586269	SCV000653450	likely benign	not provided	2024-01-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268014	SCV002550024	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000586269	SCV004236430	uncertain significance	not provided	2023-06-12	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358571	SCV001554347	uncertain significance	Polymerase proofreading-related adenomatous polyposis		no assertion criteria provided	clinical testing	The POLE p.Ala2180Val variant was identified in 1 of 448 proband chromosomes (frequency: 0.002) from individuals or families with colorectal cancer (Bourdais 2017). The variant was also identified in dbSNP (ID: rs552452448) as "With Uncertain significance allele", ClinVar (classified as benign by Integrated Genetics/Laboratory Corporation of America; as likely benign by Invitae; and as uncertain significance by GeneDx). The variant was identified in control databases in 51 of 273776 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24006 chromosomes (freq: 0.00004), Other in 1 of 6438 chromosomes (freq: 0.0002), Latino in 1 of 34412 chromosomes (freq: 0.00003), East Asian in 5 of 18858 chromosomes (freq: 0.0003), and South Asian in 43 of 30768 chromosomes (freq: 0.001), while the variant was not observed in the European, Ashkenazi Jewish, or Finnish populations. The p.Ala2180 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.