Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000472185 | SCV000563985 | pathogenic | Lynch syndrome | 2016-10-31 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exons 5-6 of the MSH6 gene. This leads to an in-frame deletion of amino acid residues 1058-1185, preserving the integrity of the reading frame. Similar deletions of exons 5-6 have been reported in individuals affected with endometrial cancer (PMID: 16885385, 22306203). This deletion removes the N-terminal portion of the ATPase domain of the MSH6 protein, including the entire ATP binding motif (PMID: 12019211); ATP hydrolysis is required for MSH6-mediated mismatch repair in vitro (PMID: 9564049, 9428522). A missense substitution p.Arg1076Cys in exon 5 has been determined to be pathogenic (PMID: 15483016, 16418736, 16525781, 21039432, 18409202, Invitae database) and an in vitro functional study shows that the p.Lys1140Arg missense change impairs MSH6-MSH2 heterodimer ATP binding and hydrolysis, ATP-dependent dissociation from mismatch-containing oligonucleotides, and mismatch repair activity. These results indicate that these amino acid residues, which are located in the region deleted by this variant, are critical to MSH6 protein function. For these reasons, this variant has been classified as Pathogenic. |