Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075999 | SCV000107009 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Multifactorial likelihood analysis posterior probability >0.99 |
| Ambry Genetics | RCV002354266 | SCV002623150 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-11-24 | criteria provided, single submitter | clinical testing | The p.G338E pathogenic mutation (also known as c.1013G>A), located in coding exon 6 of the MSH2 gene, results from a G to A substitution at nucleotide position 1013. The glycine at codon 338 is replaced by glutamic acid, an amino acid with similar properties. This variant was identified in a male proband who met Amsterdam I criteria for Lynch syndrome and was diagnosed with bladder cancer at the age of 57 as well as MSI-H colon cancer cancer at the of age 32 that demonstrated loss of both MSH2/MSH6 staining on immunohistochemistry (IHC) (Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463). Based on an internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Warren JJ et al. Mol Cell, 2007 May;26:579-92). Another alteration at the same codon, p.G338R (c.1012G>C), has been detected in individuals with family histories that met Amsterdam I/II criteria and/or had Lynch syndrome associated tumors that demonstrated loss of MSH2/MSH6 staining on IHC (Ambry internal data; Moline J et al, Gynecol. Oncol. 2013 Jul; 130(1):121-6; Pearlman R et al. J. Med. Genet., 2019 Jul;56:462-470). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Constitutional Genetics Lab, |
RCV001250033 | SCV001423958 | pathogenic | Lynch-like syndrome | 2019-07-01 | no assertion criteria provided | clinical testing |