ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.435T>G (p.Ile145Met) (rs63750124)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588226 SCV000149441 uncertain significance not provided 2017-11-07 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.435T>G at the cDNA level, p.Ile145Met (I145M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATT>ATG). This variant was observed to co-segregate with disease in one family meeting Amsterdam Criteria, with a corresponding colon tumor showing microsatellite instability and absence of MSH2 protein (Spaepen 2006). This variant was also identified in a patient with triple negative breast cancer, in co-occurrence with a pathogenic PALB2 variant (Spugnesi 2016). Additionally, this variant was observed in individuals with a personal and family history of colon cancer, with some of the colon tumors displaying microsatellite instability and/or absence of MSH2 protein on immunohistochemistry (Kariola 2003, Plevova 2004, Pinol 2005, Kurzawski 2006, Duraturo 2015). Two of these individuals were also found to carry an MSH6 missense variant of uncertain significance. In vitro mismatch repair (MMR) assays performed to assess the effect of these variants on MSH2-MSH6 interaction showed that neither MSH2 Ile145Met nor either of the MSH6 missense variants alone caused mismatch repair deficiency, but the possibility of compound pathogenicity could not be excluded (Kariola 2003). In addition, in vivo functional studies have demonstrated no reduction in steady-state levels of MSH2 protein, suggesting this variant is not pathogenic (Gammie 2007, Kansikas 2011). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies MSH2 Ile145Met as a variant of uncertain significance (Thompson 2014). MSH2 Ile145Met was observed at an allele frequency of 0.045% (57/126,682) in individuals of European (non-Finnish) ancestry in large population cohorts (Lek 2016). Since Isoleucine and Methionine share similar properties, this is considered a conservative amino acid substitution. MSH2 Ile145Met occurs at a position that is not conserved and is located in the connector domain (Lutzen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Ile145Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000588226 SCV000166282 benign not provided 2019-03-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115532 SCV000187599 likely benign Hereditary cancer-predisposing syndrome 2017-08-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene,Intact protein function observed in appropriate functional assay(s),In silico models in agreement (benign),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,Other data supporting benign classification
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212585 SCV000539684 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple papers classified as non-pathogenic, ExAC: 0.1% (38/66740) European chromosomes
Genetic Services Laboratory, University of Chicago RCV000212585 SCV000595830 uncertain significance not specified 2016-06-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212585 SCV000601480 uncertain significance not specified 2016-08-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212585 SCV000696268 likely benign not specified 2019-05-10 criteria provided, single submitter clinical testing Variant summary: MSH2 c.435T>G (p.Ile145Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 283316 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.00047 in the gnomAD database. Both of these frequencies are slightly lower than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (0.00057), allowing no conclusion about variant significance. c.435T>G has been reported in the literature in individuals affected with Lynch Syndrome, where co-segregation with the disease was observed in at least two families (Parc 2003 and Spaepen 2006). However, in these studies, not all MMR genes were analyzed and the possibility of other deleterious variants contributing to the disease phenotype cannot be excluded. Some of the reported patients have also carried other MSH6 variants (R1095H or L1354Q; both are classified as VUS by InSiGHT), and the possibility of compound pathogenicity was suggested by the authors (Kariola 2003). One breast cancer patient carried the variant of interest and PALB2 c.38_39insG/p.K14fs*29 (presumed pathogenic; Spugnesi 2016). These reports however, do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In our internal database co-occurrence with another pathogenic variant has been reported (heterozygous, MUTYH c.1187G>A, p.Gly396Asp) for this variant, however this evidence is not utilized as supportive of a benign role for this MSH2 variant of interest. Publications reported experimental evidence evaluating an impact on protein function, and demonstrated preserved MSH2-MSH6 interaction, as well as proficient MMR activity (Kariola 2003, Gammie 2007, Kansikas 2011 and Kantelinen 2012). Eleven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign (n=2) and uncertain significance (n=9)).Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000662480 SCV000784978 uncertain significance Lynch syndrome I 2017-02-28 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000588226 SCV000806042 uncertain significance not provided 2017-03-06 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115532 SCV000822053 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000076599 SCV000837819 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764421 SCV000895478 uncertain significance Lynch syndrome I; Turcot syndrome; Muir-Torré syndrome 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000115532 SCV000910574 likely benign Hereditary cancer-predisposing syndrome 2015-11-05 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148628 SCV000190343 likely benign Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research

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