ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3674C>T (p.Thr1225Met) (rs63750370)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212686 SCV000211324 uncertain significance not provided 2018-07-26 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3674C>T at the cDNA level, p.Thr1225Met (T1225M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has been identified in individuals with colorectal or endometrial cancer (Wijnen 1999, Hampel 2006, Lagerstedt Robinson 2007, Nilbert 2009, Drost 2012). The colorectal tumor from one of these individuals was shown to be microsatellite stable and immunohistochemistry revealed presence of MSH6, while an endometrial tumor was microsatellite instable, showed retention of MSH6 and MSH2 but absence of MLH1 and PMS2, and was positive for MLH1 promoter hypermethylation (Hampel 2006, Lagerstedt Robinson 2007, Houlleberghs 2017). In addition, functional assays have demonstrated that MSH6 Thr1225Met displays mismatch repair activity similar to wildtype (Drost 2012, Houlleberghs 2017). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertain due to insufficient evidence for classification (Thompson 2014). MSH6 Thr1225Met was observed at an allele frequency of 0.015% (19/126,534) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Thr1225Met is located within the ATPase domain and the Magnesium ion binding site (Kariola 2002, Warren 2007, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Thr1225Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160696 SCV000212834 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000524182 SCV000254319 uncertain significance Hereditary nonpolyposis colon cancer 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1225 of the MSH6 protein (p.Thr1225Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs63750370, ExAC 0.02%). This variant was reported in individuals affected with Lynch syndrome (PMID: 18566915, 17312306, 10508506, 16885385, 27601186) and in an individual affected with prostate cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 89443). Experimental studies have shown that this missense change does not impact MSH6 mismatch repair activity in vitro (PMID: 22102614). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000410774 SCV000489095 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-08-19 criteria provided, single submitter clinical testing
Color RCV000160696 SCV000685429 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780485 SCV000917775 uncertain significance not specified 2018-08-28 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3674C>T (p.Thr1225Met) results in a non-conservative amino acid change located in the C-terminal region (IPR000432) of the encoded protein sequence and affects the ATPase domain (Houlleberghs 2017). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 276978 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.00015 in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), suggesting that the variant might be a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.3674C>T, has been reported in the literature in individuals affected with Lynch Syndrome (Wijnen 1999, Hampel_2006, Nilbert_2009, Lagerstedt-Robinson_2007 and 2016). An endometrial tumor sample from one patient showed microsatellite instability but showed retention of MSH6 and MSH2 and loss of MLH1/PMS2 with MLH1 promoter hypermethylation (Wijnen_1999). Thus these data do not allow any conclusion about variant significance. At least two publications reported experimental evidence evaluating an impact on protein function, and showed no damaging effect of this variant (Drost 2011, Houlleberghs 2017). Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.

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