ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4730A>C (p.Glu1577Ala)

gnomAD frequency: 0.00049  dbSNP: rs5744948
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000657111 SCV000289401 likely benign not provided 2024-02-01 criteria provided, single submitter clinical testing
GeneDx RCV000657111 SCV000293810 likely benign not provided 2020-12-16 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 19966286, 20951805)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236705 SCV000602056 benign not specified 2017-03-29 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000679006 SCV000805302 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-27 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004529408 SCV000806790 likely benign POLE-related disorder 2023-03-30 no assertion criteria provided clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000657111 SCV001549882 uncertain significance not provided no assertion criteria provided clinical testing The POLE p.Glu1577Ala variant was identified in dbSNP (ID: rs5744948) and ClinVar (classified as benign by Quest Diagnostics Nichols Institute San Juan Capistrano, likely benign by Invitae and uncertain significance by GeneDx, Prevention Genetics and True Health Diagnostics), but was not identified in Cosmic. The variant was identified in control databases in 50 of 282236 chromosomes at a frequency of 0.0001772 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 48 of 24740 chromosomes (freq: 0.00194) and Latino in 2 of 35388 chromosomes (freq: 0.000057), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other, or South Asian populations. The p.Glu1577 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Glu1577Ala 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. A functional study in yeast found no significant effect on DNA polymerase function or mutagenesis with the variant compared to wildtype (Daee_2010_PMID:19966286). 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.

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