ClinVar Miner

Submissions for variant NM_000401.3(EXT2):c.1687G>A (p.Glu563Lys) (rs148711133)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000250542 SCV000317230 likely benign not specified criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726040 SCV000341407 uncertain significance not provided 2016-05-14 criteria provided, single submitter clinical testing
Invitae RCV001081789 SCV001106710 likely benign Multiple exostoses type 2 2019-12-31 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000726040 SCV001550752 likely benign not provided no assertion criteria provided clinical testing The EXT2 p.E563K variant was identified in 1 individual with Müllerian adenosarcoma (Howitt_2015_PMID:25231023). The variant was identified in dbSNP (ID: rs148711133) and ClinVar (classified as likely benign by Prevention Genetics and Invitae; and as uncertain significance by EGL Genetic Diagnostics). This variant was not found in COSMIC. The variant was identified in control databases in 166 of 282838 chromosomes (1 homozygous) at a frequency of 0.0005869, and was observed at the highest frequency in the European (non-Finnish) population in 148 of 129156 chromosomes (freq: 0.001146) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.E563 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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