Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Department of Pathology and Laboratory Medicine, |
RCV001354993 | SCV001549740 | pathogenic | Lynch syndrome | no assertion criteria provided | clinical testing | The c.1277-?_1386+?del variant (chr2.hg38.g.47445245-?_47445336+?del) results in a deletion of exon 8, 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 27 of 3090 proband chromosomes (frequency: 0.009) from individuals or families with colorectal cancer or other Lynch syndrome associated cancers (Borelli 2013, Di Fiore 2004, Hampel 2005, Kurzawski 2006, Stella 2007, Taylor 2003, van der Klift 2005, Woods 2005). The variant was also identified in HGMD, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, and in the ClinVar database as a pathogenic mutation (reviewed by an expert panel). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 427 and leads to a premature stop codon 4 codons downstream. This alteration is then predicted to result in a truncated or 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 addition, tumour analyses showed high microsatellite instability and loss of MSH2 and MSH6 expression (Borelli 2013, Hampel 2005, Kurzawski 2006, Stella 2007), and four families in one study showed segregated of the deletion with disease (Woods 2005). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. |