ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1461C>G (p.Asp487Glu) (rs35107951)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131869 SCV000186924 likely benign Hereditary cancer-predisposing syndrome 2017-05-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Color RCV000131869 SCV000910759 benign Hereditary cancer-predisposing syndrome 2016-04-19 criteria provided, single submitter clinical testing
Counsyl RCV000411837 SCV000488403 uncertain significance Lynch syndrome I 2016-03-18 criteria provided, single submitter clinical testing
GeneDx RCV000590052 SCV000211181 uncertain significance not provided 2018-10-31 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1461C>G at the cDNA level, p.Asp487Glu (D487E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAG). This variant has been observed in at least two men with a history of later-onset colon cancer and at least one woman with a history of endometrial cancer (Hampel 2005, Hampel 2006). However, all three tumors exhibited absence of MLH1 and PMS2 with retention of MSH2 via immunohistochemistry and showed MLH1 promoter hypermethylation, suggesting that the cancers were unrelated to this MSH2 variant. This variant has also been observed in individuals with personal and/or family histories of early-onset colorectal cancer, breast cancer, and/or ovarian cancer (Pal 2012, Chubb 2015, Shirts 2016). While MSH2 Asp487Glu has been shown to result in decreased mismatch repair efficiency compared to wild-type controls, similar functional results were observed for a known neutral MSH2 variant in this same study (Kantelinen 2012). MSH2 Asp487Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Asp487Glu is located within the clamp domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on the currently available evidence, it is unclear whether MSH2 Asp487Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590052 SCV000696215 uncertain significance not provided 2016-08-08 criteria provided, single submitter clinical testing Variant summary: The c.1461C>G (p.Asp487Glu) in MSH2 gene is a missense change that involves a non-conserved nucleotide and 5/5 in silico tools predict benign outcome. The variant of interest is located within the clamp domain, which is a region that also interacts with MSH3 and MSH6. The variant is present in control dataset of ExAC at a low frequency of 0.000025 (3/121534 chrs tested) which does not exceed the estimated maximum allele frequency for a pathogenic allele in this gene (0.0005). This variant has been observed in at least 3 pts with HNPCC without clear contributory causality effect of this variant into disease pathogenesis (lack of MLH1 and PMS2 possibly due to confirmed MLH1 promoter hypermethylation with retention of MSH2 signal via ICH). In functional studies this variant showed moderate reduction of MMR activity compared to wt control. Many reputable databases/clinical laboratories classified this variant as VUS. Taking together, the variant was classified as VUS.
Invitae RCV000524343 SCV000218787 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 487 of the MSH2 protein (p.Asp487Glu). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs35107951, ExAC 0.004%). This variant has been reported in individuals affected with breast, ovarian, endometrial, and colorectal cancer (PMID: 26845104, 16885385, 23047549, 25559809, 15872200). ClinVar contains an entry for this variant (Variation ID: 90674). Experimental studies have shown that this missense change decreases DNA repair efficiency in vitro. However, the same study reported a similar result for a common polymorphism in MSH2, making the significance of these observations uncertain (PMID: 22581703). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for mismatch repair genes (PMID: 22290698), all suggest that this missense change is likely to be tolerated. 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.
PreventionGenetics RCV000590052 SCV000806000 uncertain significance not provided 2017-01-17 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000131869 SCV000805266 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-18 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000076170 SCV000266192 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing

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