ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.435T>G (p.Ile145Met) (rs63750124)

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Total submissions: 18
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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 RCV001085983 SCV000166282 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115532 SCV000187599 likely benign Hereditary cancer-predisposing syndrome 2020-04-02 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
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 RCV000588226 SCV000601480 uncertain significance not provided 2020-01-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212585 SCV000696268 likely benign not specified 2020-09-29 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 0.00032 in 251922 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.00049 in the gnomAD database. Both of these frequencies are slightly lower than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (0.00057), allowing no conclusion about variant significance. c.435T>G has been reported in the literature in individuals affected with Nonpolyposis Colorectal Cancer, where co-segregation with the disease was observed in at least two families (examples-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 (e.g. Kariola 2003). A breast cancer patient was reported to carry the variant of interest and PALB2 c.38_39insG/p.K14fs*29 (presumed pathogenic; Spugnesi 2016). These reports do not provide unequivocal conclusions about association of the variant with Nonpolyposis Colorectal Cancer. In our internal database, co-occurrence with another pathogenic variant has been reported (heterozygous, MUTYH c.1187G>A, p.Gly396Asp), however this evidence is not utilized as supportive of a benign role for this MSH2 variant of interest. Multiple publications have reported experimental evidence evaluating an impact on protein function, and demonstrated preserved MSH2-MSH6 interaction, as well as proficient MMR activity (examples- Kariola 2003, Gammie 2007, Kansikas 2011 and Kantelinen 2012). 14 other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant with conflicting assessments (benign/likely benign, n=3; uncertain significance, n=11). 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 Health, Inc RCV000115532 SCV000910574 likely benign Hereditary cancer-predisposing syndrome 2015-11-05 criteria provided, single submitter clinical testing
Mendelics RCV000662480 SCV001135702 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000662480 SCV001297028 uncertain significance Lynch syndrome I 2019-02-21 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV001262752 SCV001440734 uncertain significance Breast carcinoma 2019-01-01 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148628 SCV000190343 likely benign Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358588 SCV001554370 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MSH2 p.Ile145Met variant was identified in 2 of 628 proband chromosomes (frequency: 0.003) from individuals or families with hereditary non-polyposis colorectal cancer or renal cell carcinoma (Spaepen 2006, Rubio-Del-Campo 2008). The variant was also identified in dbSBP (ID: rs63750124) classified as “With Uncertain significance”, ClinVar (1x benign: Invitae; 2x likely benign: Ambry Genetics, University of Washington Medical Center; 3x uncertain signirnficance: InSiGHT, GeneDx, Partners HealthCare), UMD-LSDB (biological significance: unclassified/unknown variant), Insight Colon Cancer Gene Variant Database (28 entries, class 3, uncertain significance), Mismatch Repair Genes Variant Database (5 references) databases. The variant was not identified in Genesight-COGR, MutDB, Zhejiang Colon Cancer Database, Insight Hereditary Tumors Database, or COSMIC databases. The variant was identified by our laboratory in 1 individual with endometrial cancer with MSH2/MSH6 deficiency by IHC. The variant was identified in control databases in 82 of 277196 chromosomes at a frequency of 0.0003 in the following populations: European (Non-Finnish) in 57 of 126682 chromosomes (freq. 0.00045), Latino in 12 of 34418 chromosomes (freq. 0.0003), European (Finnish) in 5 of 25792 chromosomes (freq. 0.0002), African in 3 of 24038 chromosomes (freq. 0.0001), and South Asian in 1 of 30782 chromosomes (freq. 0.00003), and other in 4 of 6466 chromosomes (freq. 0.0006) but was not seen in Ashkenazi Jewish and East Asian populations, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Functional studies using combined co-immunoprecipitation/ Western blot analysis shows this variant combined with wild type MSH6 actually increases protein translation, and the protein demonstrates an increased proportion of the MSH2 component. In addition, a MMR functional assay demonstrates that this variant is as functional as wild type protein, suggesting that, provided that protein levels are adequate, this variant is non-pathogenic (Kariola 2003). A yeast MMR assay demonstrates this variant retains 89% activity relative to wild type, supporting a non-pathogenic classification (Gammie 2007). A review of prior studies finds this variant to be non-pathogenic by MMR assay, in silico analysis, expression and interaction analysis, though it is noted that this variant has been found in carriers of other MMR gene variations (Kansikas 2010). Expression of MSH2 protein is demonstrated to be present by IHC in a non-Amsterdam criteria/non-Bethesda Guidelines patient with this variant (Pinol 2005). The p.Ile145Met residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. This residue is not located in an MSH2-MSH6 interaction region (Wielders 2013). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located within the DNA mismatch repair protein MSH2 functional domain, increasing the likelihood that it may have clinical significance. 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 benign role for this variant. This variant is classified as likely benign.

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