Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000491347 | SCV000580128 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2016-03-28 | criteria provided, single submitter | clinical testing | The c.3701_3706dupAACTTG variant, located in coding exon 8 of the MSH6 gene, results from a duplication of six nucleotides between positions 3701 and 3706. This results in the duplication of two amino acids, glutamate and leucine, between codons 1234 and 1235. Structural analysis indicated that this duplication occurs at the interaction interface between the MSH2 protein and MSH6 protein in the ATPase domain. The two inserted amino acids are predicted to alter the protein's structure and the ability for the MSH6 protein to dimerize with the MSH2 protein (Warren JJ et al. Mol. Cell 2007 May;26(4):579-92). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13,006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 115000 alleles tested) in our clinical cohort. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Department of Pathology and Laboratory Medicine, |
RCV000502171 | SCV000592652 | likely pathogenic | Carcinoma of colon | no assertion criteria provided | clinical testing | The MSH6, p.Glu1234_Leu1235dup variant was not identified in the literature nor was the variant identified in dbSNP database, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, COSMIC, MutDB, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, ClinVar database, or UMD. The c.3701_3706dupAACTTG variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing however, this information is not predictive enough to rule out pathogenicity. The residues that are duplicated are conserved in mammals and are part of the DNA mismatch repair protein MutS, C-terminal locus and variants at this position may affect protein function. This variant is an in-frame duplication resulting in the addition of a glutamine and a leucine (Glu and Leu) residue at codon 1234 to 1235; however, the impact of this alteration on MSH6 protein function is not known. This variant has been observed in one family in recessive form in one family with features of biallelic MMR syndrome increasing the likelihood this variant may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time athough we would lean towards a more pathogenic role for this variant. This variant is classified as predicted pathogenic. |