Description
The p.Asn223Ser variant was identified in one database InSiGHT Colon Cancer Gene Variant Database 2X as an “uncertain” variant. It was not found in any of the following databases: dbSNP, 1000 Genomes Project, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, HGMD, COSMIC, MutDB, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “Zhejiang Colon Cancer Database”, the ClinVar database, GeneInsight VariantWire database, and UMD. It was included in two bioinformatic studies that predicted the impact of missense variants in MSH6. Both studies concluded that the variant has no impact or is neutral (Terui 2013, Ali 2012). The p.Asn223 residue is not conserved in mammals or other vertebrates and the variant amino acid Serine (Ser) is present in zebrafish, increasing the likelihood that this variant does not have clinical significance. In addition, 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. One of 5 in-silico splicing software predicts the creation of a 5' splice site, but this information is not very accurate. This variant was found in our laboratory to co-occur in with a known pathogenic variant c.3957dupA, increasing the likelihood that this variant does not have clinical significance. 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 predicted benign.
# | Sample | Method | Observation |
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Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
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1 | unknown | yes | not provided | not provided | not provided | | 1 | not provided | not provided | not provided |