Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001014118 | SCV001174792 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2018-01-17 | criteria provided, single submitter | clinical testing | The p.G674S variant (also known as c.2020G>A), located in coding exon 13 of the MSH2 gene, results from a G to A substitution at nucleotide position 2020. The glycine at codon 674 is replaced by serine, an amino acid with similar properties. In an in vitro study, ATP binding and ATPase activity were both reduced for this alteration, but no defect in mismatch recognition was seen (Heinen CD et al. Cancer Cell, 2002 Jun;1:469-78). Studies using the yeast equivalent allele, p.G693S, reported a defect in mismatch repair for this alteration (Gammie AE et al. Genetics, 2007 Oct;177:707-21; Drotschmann K et al. Proc. Natl. Acad. Sci. U.S.A., 1999 Mar;96:2970-5). Another alteration at the same codon, p.G674D, has been reported in a proband who met clinical criteria for Lynch syndrome (Raedle J et al. Ann. Intern. Med., 2001 Oct;135:566-76; Brieger A et al. Fam. Cancer, 2011 Sep;10:591-5) and was shown to have reduced function in several studies (Studamire B et al. Mol. Cell. Biol., 1999 Nov;19:7558-67; Bowers J et al. J. Mol. Biol., 2000 Sep;302:327-38; Kijas AW et al. J. Mol. Biol., 2003 Aug;331:123-38; Gammie AE et al. Genetics, 2007 Oct;177:707-21). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analysis (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV001379379 | SCV001577173 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2020-08-14 | criteria provided, single submitter | clinical testing | 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. This variant has been reported to affect MSH2 protein function (PMID: 12124176, 17720936, 10077621). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly674 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11601928, 21598002, 10523644, 12875840, 24362816, 24362816). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 820546). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 674 of the MSH2 protein (p.Gly674Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. |