ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2090G>A (p.Cys697Tyr) (rs63750398)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000490613 SCV000579295 likely pathogenic Lynch syndrome I 2018-03-09 reviewed by expert panel curation Class 4 - Likely Pathogenic Classification using multifactorial probability: 0.987
Ambry Genetics RCV000167253 SCV000218093 likely pathogenic Hereditary cancer-predisposing syndrome 2015-07-01 criteria provided, single submitter clinical testing The p.C697Y variant (also known as c.2090G>A), located in coding exon 13 of the MSH2 gene, results from a G to A substitution at nucleotide position 2090. The cysteine at codon 697 is replaced by tyrosine, an amino acid with highly dissimilar properties. To our knowledge, this variant has not been reported in the literature to date. However, two other alterations at this same codon, (p.C697F and p.C697R), have 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 B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). The p.C697Y alteration is part of the ATPase domain, which is a structurally important region (Warren JJ et al. Mol. Cell (2007) 26, 579-592). According to internal structural analysis, p.C697Y is located in a key structural position and is indicated to be even more structurally destabilizing than the other alterations at this same codon (p.C697F and p.C697R) (Ambry internal data). This variant, p.C697Y, was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 65000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV000167253 SCV000690045 likely pathogenic Hereditary cancer-predisposing syndrome 2020-02-05 criteria provided, single submitter clinical testing
Invitae RCV000817438 SCV000957998 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 697 of the MSH2 protein (p.Cys697Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333), and an individual undergoing testing for Lynch syndrome (PMID: 28514183). ClinVar contains an entry for this variant (Variation ID: 187518). Experimental studies in mouse embryonic stem cells have shown that this missense change causes low MSH2 protein levels as compared to wild-type and deficient mismatch repair activity (PMID: 26951660). Based on a multifactorial likelihood algorithm using genetic/in silico/statistical/segregation data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). Variants that disrupt the p.Cys697 amino acid residue in MSH2 have been observed in affected individuals (PMID: 21239990, 17101317, Invitae). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.
CZECANCA consortium RCV001270946 SCV001451750 likely pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing

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