ClinVar

Description

The MSH2 c.1-?_1076+?del variant (chr:2 g.47630331_47643568del GRCh37) results in a deletion of exons 1-6, although the precise breakpoints of this deletion were not determined, nor were the effects of this variant on the resulting mRNA or protein product determined. The variant was identified in 15 of 996 proband chromosomes (frequency: 0.02; Wagner 2003 PMID:12658575, Van Der Klift 2005 PMID:15942939) with Lynch Syndrome. The variant was also identified in ClinVar (2x as pathogenic by InSiGHT and OMIM), in UMD-LSDB (22x as Causal) and in MutDB. In addition the MSH2 exon 1-6 deletion variant was identified as a founder variant in the United States where 9 probands connected 566 family members including 61 known carriers (Lynch 2004 PMID:14871915). Tumor sequencing was performed on a right sided colon cancer tumor identified in a 32 year old with a germline MSH2 exon 1-6 deletion and the tumor displayed loss of heterozygosity of MSH2 (Lui 1995 PMID:7704024). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c1-?_1076+?del (exons 1-6 deletion) variant is predicted to result in an absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.