Submissions for variant NM_000179.3(MSH6):c.3860_3882dup (p.Pro1295fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV003585642	SCV004357767	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	This variant inserts 23 nucleotides in exon 9 of the MSH6 gene, creating a frameshift and premature translation stop signal. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein lacking the last 27 amino acids, expected to disrupt the ATPase and MSH2-binding domains (PMID: 12019211, 21120944). However, the clinical relevance of the loss of this C-terminal region is not known. This variant has been reported in individuals affected with endometrial cancer (PMID: 27398995). One patient showed microsatellite instability and loss of MSH6/MSH2 via immunohistochemistry analysis. The other patient showed loss of MSH6 in a microsatellite stable tumor. In addition, truncating variants occurring downstream of this variant are known to be disease-causing (ClinVar variation ID: 89496, 419474, 218076). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV004011500	SCV004835155	pathogenic	Lynch syndrome	2023-07-13	criteria provided, single submitter	clinical testing	This variant inserts 23 nucleotides in exon 9 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein, deleting the last 27 amino acids. Although functional studies have not been reported, this variant is expected to disrupt the ATPase and MSH2-binding domains (PMID: 12019211, 21120944). This variant has been reported in individuals affected with endometrial cancer (PMID: 27398995). In addition, truncating variants occurring downstream of this variant are known to be disease-causing (ClinVar variation ID: 218076, 89498, 525790). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.