ClinVar

Description

The MSH6 p.Gly273Glu variant was not identified in the literature nor was it identified in the COGR, COSMIC, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs769610487) as “With Uncertain significance allele”, ClinVar and Clinvitae databases (2x classified as uncertain significance by Ambry Genetics and Invitae). The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Consortium (Feb 27, 2017). The p.Gly273Glu residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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, HumanSpliceFinder) do not predict a difference in splicing. The variant is located within the DNA mismatch repair protein Msh6 functional domain. 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.