ClinVar

Description

The MSH6 p.Thr764Ser variant was not identified in the literature nor was it identified in the following databases: dbSNP, ClinVar, COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene, Zhejiang Colon Cancer, Mismatch Repair Genes, or the Insight Hereditary Tumors Databases. The variant was identified in control databases in 3 of 245886 chromosomes at a frequency of 0.00001 increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017); it was observed in the South Asian population in 3 of 30782 chromosomes and was not seen in other populations. The p.Thr764 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood to impact the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.