ClinVar

Description

The c.942+2_942+11del10 pathogenic mutation, located in intron 5 of the MSH2 gene, results from a deletion of 10 nucleotides within intron 5 of the MSH2 gene. Due to the polyA region from c.942+3 to c.942+29, this deletion only affects the c.942+2 position of the canonical donor site. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown; however, the impacted region is critical for protein function (Ambry internal data). Two alterations impacting the same donor site (c.942+2T>C and c.942+2T>A) have been detected in individuals whose Lynch-related tumors demonstrated high microsatellite instability, loss of MSH2/MSH6 expression on immunohistochemistry and family histories were consistent with Lynch syndrome (Ambry internal data; de Lellis L at al. PLoS ONE 2013;8(11):e81194; Castillejo MI et al. eJIFCC Volume 27 no 1; February 2016). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.