ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2576_2584del (p.Glu859_Gln861del) (rs587781278)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128935 SCV000172806 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-21 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000656885 SCV000211233 uncertain significance not provided 2017-11-28 criteria provided, single submitter clinical testing This in-frame deletion of nine nucleotides is denoted MSH2 c.2576_2584delAATCGCAAG at the cDNA level and p.Glu859_Gln861del (E859_Q861del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GGAG[delAATCGCAAG]GATA. This variant has been reported in an individual with endometrial cancer and in one individual with colorectal cancer diagnosed under age 50; however, immunohistochemical analysis of the colon tumor showed presence of MLH1, MSH2 and MSH6 proteins (Casey 2005, Ring 2016). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). This deletion is located in the helix-turn-helix domain (Lutzen 2008, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider MSH2 Glu859_Gln861del to be a variant of uncertain significance.
Invitae RCV000168369 SCV000219059 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-01-02 criteria provided, single submitter clinical testing
Counsyl RCV000410609 SCV000489404 uncertain significance Lynch syndrome I 2016-10-03 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000202257 SCV000539685 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: 1 report - no effect on protein expression; ClinVar: 2 VUS
Color RCV000128935 SCV000685059 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-02 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000410609 SCV000781777 uncertain significance Lynch syndrome I 2016-11-01 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000664314 SCV000788247 likely benign Lynch syndrome 2018-04-01 criteria provided, single submitter research The MSH2 gene variant designated as NM_000251.2:c.2576_2584delAATCGCAAG (p.E859_Q861del) is classified as likely benign. Cosegregation analysis of one observed family was performed using (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 0.256:1 favoring a benign classification (Thompson et al., 2003, PMID:2900794). Data from a large reference laboratory cohort indicates that this variant was identified in many more individuals without MSH2 associated cancers than individuals affected with MSH2 associated cancers. In addition, the genomic position of this variant is not highly conserved, which also supports benign classification. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MSH2 function or cause an increased risk of Lynch syndrome associated cancers. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Integrated Genetics/Laboratory Corporation of America RCV000202257 SCV001431889 uncertain significance not specified 2020-08-07 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2576_2584delAATCGCAAG (p.Glu859_Gln861del) results in an in-frame deletion that is predicted to remove three amino acids from helix-turn-helix domain in the encoded MSH2 protein. The variant allele was found at a frequency of 2e-05 in 251448 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2576_2584delAATCGCAAG has been reported in the literature in individuals affected with colon cancer and endometrial carcinoma (Plevova_2004, Casey_2005, Poynter_2008, Ring_2016). However, immunohistochemical analysis showed that there is no effect on expression of MLH1, MSH2 and MSH6 proteins (Plevova_2004, Casey_2005, Poynter_2008). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (7x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202257 SCV000257180 uncertain significance not specified no assertion criteria provided research
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000410609 SCV000745645 uncertain significance Lynch syndrome I 2017-03-24 no assertion criteria provided clinical testing

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