Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000767200 | SCV000211210 | likely pathogenic | not provided | 2021-11-29 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11208710, 18822302, 21120944, 26648449) |
Ambry Genetics | RCV000491255 | SCV000580494 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-09-26 | criteria provided, single submitter | clinical testing | The p.G164W pathogenic mutation (also known as c.490G>T), located in coding exon 3 of the MSH2 gene, results from a G to T substitution at nucleotide position 490. The glycine at codon 164 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration was identified in individuals with early onset colorectal cancer that met Amsterdam I/II criteria for Lynch syndrome and/or had MSI-H tumors demonstrating loss of MSH2 on immunohistochemistry (IHC) (Ambry internal data; Jansen AM et al. Eur. J. Hum. Genet., 2016 07;24:1089-92; Terdiman JP et al. Gastroenterology, 2001 Jan;120:21-30). Another alteration at the same position, p.G164R, has been reported as a pathogenic mutation based on identification in individuals with Lynch syndrome and deficient function in an in vitro mismatch repair assay (Mangold et. al, Int J Cancer. 2005; 116(5): 692-702, Ou et al, Hum Mutat. 2007; 28(11): 1047-54, Lucci-Cordisco et. al., Cancer Biomarkers. 2006; 2:11-27; Ollila et al., Gastroent. 2006; 131: 1408). Based on an internal structural assessment, this alteration is in the core of the connector domain and is highly destabilizing in an established sensitive region (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Invitae | RCV001060501 | SCV001225194 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-07-25 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly164 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1710317, 15849733, 18951462; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 91110). This missense change has been observed in individuals with colorectal cancer (PMID: 11208710, 26648449; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 164 of the MSH2 protein (p.Gly164Trp). |
Department of Pathology and Laboratory Medicine, |
RCV000168725 | SCV000592466 | likely pathogenic | Familial colorectal cancer | no assertion criteria provided | clinical testing | The MSH2 p.Gly164Trp variant was identified in 2 of 346 proband chromosomes (frequency: 0.006) from individuals or families with lynch syndrome (Terdiman 2001, Jansen 2016). The variant was identified in dbSNP (rs63750582) as 'Auwith pathogenic allele'Au and ClinVar (classified as uncertain significance by GeneDx and InSiGHT and pathogenic by Ambry Genetics). The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant was identified by our laboratory in two family members both with a MSH2-deficient colorectal tumour. In other laboratories, a pathogenic variant was observed at the same loci with a different protein change (p.Gly164Arg). In addition, the variant was also observed in an individual with MSH2/MSH6 deficient tumor and a second MSH2 somatic pathogenic variant was also identified (c.1511-1G>T, Jansen 2016). The p.Gly164 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic | |
Zotz- |
RCV003444198 | SCV004171661 | pathogenic | Lynch syndrome 1 | 2023-11-24 | no assertion criteria provided | clinical testing |