Submissions for variant NM_000251.3(MSH2):c.2576_2584del (p.Glu859_Gln861del)

dbSNP: rs587781278

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128935	SCV000172806	likely benign	Hereditary cancer-predisposing syndrome	2022-02-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000656885	SCV000211233	uncertain significance	not provided	2023-05-08	criteria provided, single submitter	clinical testing	In-frame deletion of 3 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Observed in individuals with endometrial or colorectal cancer (Plevova et al., 2004; Casey et al., 2005; Ring et al., 2016); Located in the critical helix-turn-helix domain (Lutzen et al., 2008; Kansikas et al., 2011); This variant is associated with the following publications: (PMID: 15713769, 18822302, 27720647, 27443514, 30374176, 18990764, 15254659, 24194902, 21120944)
Invitae	RCV000168369	SCV000219059	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000410609	SCV000489404	uncertain significance	Lynch syndrome 1	2016-10-03	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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 Diagnostics, LLC DBA Color Health	RCV000128935	SCV000685059	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of three amino acids (Glu859-Gln861) in exon 15 of the MSH2 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in at least one individual each affected with endometrial and early onset colorectal cancer, in the latter case the tumor sample showed the presence of MSH2 by immunohistochemistry (PMID: 15713769, 18990764, 27443514). A multifactorial analysis based on family study data has reported this variant as likely benign due in part to cosegregation likelihood ratio of 0.2554 from one observed family (PMID: 30374176). This variant has been identified in 6/282854 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000410609	SCV000781777	uncertain significance	Lynch syndrome 1	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 analyze.myvariant.org (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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Genetic Services Laboratory, University of Chicago	RCV000202257	SCV002069949	uncertain significance	not specified	2019-12-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128935	SCV002534490	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-17	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410609	SCV004018304	likely benign	Lynch syndrome 1	2023-03-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656885	SCV004220987	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	This variant results in the in-frame deletion of three amino acids from the MSH2 protein, and has been reported in the published literature in individuals with endometrial cancer (PMID: 27443514 (2016)), and colorectal cancer in which the tumors were immunohistochemically positive for MSH2 expression (PMIDs: 18990764 (2008), 15713769 (2005), 15254659 (2004)). In a family study, this variant was characterized as being likely benign based on multifactorial analysis, and was identified in a cancer-free 72 year-old individual as well as in family members with colon polyps and pancreatic cancer (PMID: 30374176 (2019)). The frequency of this variant in the general population, 0.000039 (5/129166 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
CeGaT Center for Human Genetics Tuebingen	RCV000656885	SCV005042201	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	MSH2: PM4, BP4
Mayo Clinic Laboratories, Mayo Clinic	RCV000202257	SCV000257180	uncertain significance	not specified		no assertion criteria provided	research
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000410609	SCV000745645	uncertain significance	Lynch syndrome 1	2017-03-24	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000656885	SCV001924456	uncertain significance	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000410609	SCV004171627	uncertain significance	Lynch syndrome 1	2023-11-24	no assertion criteria provided	clinical testing