Submissions for variant NM_000251.3(MSH2):c.2090G>T (p.Cys697Phe)

dbSNP: rs63750398

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076385	SCV000107412	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV000571689	SCV000669699	pathogenic	Hereditary cancer-predisposing syndrome	2020-04-02	criteria provided, single submitter	clinical testing	The p.C697F pathogenic mutation (also known as c.2090G>T), located in coding exon 13 of the MSH2 gene, results from a G to T substitution at nucleotide position 2090. The cysteine at codon 697 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been found to have moderate segregation with disease in families that met Amsterdam criteria for Lynch syndrome. Tumor samples from at least one affected individual in each family demonstrated high microsatellite instability (Wehner M et al. Hum. Mutat., 1997;10:241-4; Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17; Ollila S et al. Int. J. Oncol., 2006 Jan;28:149-53). Several studies performed with this variant demonstrated reduced mismatch repair activity when compared to wild type and defective DNA mismatch binding (Ollila S et al. Int. J. Oncol., 2006 Jan;28:149-53; Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17; Drost M et al. Hum. Mutat., 2012 Mar;33:488-94; Lützen A et al. Mutat. Res., 2008 Oct;645:44-55; Ollila S et al. Hum. Mutat., 2008 Nov;29:1355-63). This alteration has also been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson BA et al. Nat. Genet., 2014 Feb;46:107-15). The p.C697F alteration is part of the ATPase domain, which is a structurally important region (Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17). Based on internal structural analysis, this variant is significantly more destabilizing than nearby known pathogenic variants (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). 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.
Color Diagnostics, LLC DBA Color Health	RCV000571689	SCV001354540	pathogenic	Hereditary cancer-predisposing syndrome	2019-07-03	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with phenylalanine at codon 697 of the MSH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant causes deficient mismatch repair activity, reduced protein expression, and abnormal cellular localization (PMID: 10469597, 16327991, 17101317, 17720936, 18822302, 18951462, 22102614). This variant has been reported in more than 10 individuals affected with colorectal cancer, endometrial cancer, and sebaceous carcinoma (PMID: 10323887, 11231323, 11859205, 12436451, 15235030, 16327991, 17101317, 18566915, 9298827). Microsatellite instability has been demonstrated in more than 5 tumor samples from these individuals (PMID: 11231323, 11859205, 12436451, 16327991, 17101317). Immunohistochemistry has demonstrated loss of MSH2 protein expression in more than 5 tumor samples (PMID: 11859205, 12436451, 15235030, 16327991, 17101317). Different variants affecting the same position (p.Cys697Tyr and p.Cys697Arg) are considered to be disease-causing (ClinVar variation ID: 187518 and 90882), suggesting that cysteine at this position is important for protein structure and function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Invitae	RCV003593899	SCV004293898	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 697 of the MSH2 protein (p.Cys697Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 9298827, 16327991, 17101317). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90883). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17101317, 18951462, 22102614). For these reasons, this variant has been classified as Pathogenic.