ClinVar

Description

The p.A1236P variant (also known as c.3706G>C), located in coding exon 8 of the MSH6 gene, results from a G to C substitution at nucleotide position 3706. The alanine at codon 1236 is replaced by proline, an amino acid with highly similar properties. This variant has been identified in a proband who met Amsterdam II criteria for Lynch syndrome and tumor demonstrated high microsatellite instability with loss of MSH6 expression by immunohistochemistry (Pastrello C et al. Genet Med, 2011 Feb;13:115-24). In addition, this variant has been identified in at least one proband whose Lynch syndrome-associated tumor demonstrated loss of MSH6 expression by immunohistochemistry (Ambry internal data). However, this variant has also been identified in a proband whose late-onset Lynch syndrome-associated tumor demonstrated high microsatellite instability and loss of MLH1/PMS2 expression by immunohistochemistry (Grandval P et al. Database (Oxford), 2013 May;2013:bat036). Based on internal structural analysis, p.A1236P is moderately destabilizing to the local structure (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.