ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.991A>G (p.Asn331Asp) (rs267607938)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000662836 SCV000107815 uncertain significance Lynch syndrome I 2018-06-13 reviewed by expert panel curation Variant reclassification due to new tumour Likelihood Ratios: Multifactorial likelihood analysis posterior probabilty is in class 3. (0.091)
Ambry Genetics RCV000130283 SCV000185128 likely benign Hereditary cancer-predisposing syndrome 2018-04-13 criteria provided, single submitter clinical testing Does not segregate with disease in family study (genes with incomplete penetrance);In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV000524429 SCV000548264 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 331 of the MSH2 protein (p.Asn331Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs267607938, ExAC 0.01%). This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 16736289, 18561205) and breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 91271). An algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be tolerated (PMID: 22290698). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. In summary, this variant has uncertain impact on MSH2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000588648 SCV000567340 uncertain significance not provided 2018-06-27 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.991A>G at the cDNA level, p.Asn331Asp (N331D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as likely benign, incorporating segregation data and tumor studies from a kindred reported by Spaepen et al. (2006) (Thompson 2014). While the authors report the variant as not segregating with disease, only three relatives were tested and their disease status is unknown. Tumor studies were limited to one colon tumor, which demonstrated microsatellite stability and normal MLH1 and MSH2 expression by immunohistochemistry. This variant was also reported in a cohort of patients meeting Amsterdam criteria or having a microsatellite unstable colon tumor, and was shown to not affect splicing in a minigene assay (Tournier 2008). This variant was also observed in at least one individual with breast cancer (Tung 2015). MSH2 Asn331Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the Lever domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Despite some evidence suggesting neutrality, based on currently available evidence, we consider this to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000790630 SCV000696297 uncertain significance not specified 2019-04-30 criteria provided, single submitter clinical testing Variant summary: MSH2 c.991A>G (p.Asn331Asp) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251462 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. 5/5 computational tools predict no significant impact on normal splicing and ESE finder predicts that this variant may eliminate a SRp55 site and create a SRp40 site. These predictions have been tested functionally through a minigene assay which confirmed that the variant does not affect splicing, despite splicing computational tools suggesting ESE sites are predicted to be affected (Tournier_2008). c.991A>G has been reported in the literature in individuals affected with Lynch Syndrome and breast cancer (Tung_2015, Tournier_2008, Spaepen_2006). One of the studies carried out additional analysis: tumor tissue from a patient was tested for microsatellite instability (0 of 10 loci were unstable), MSH2 protein expression (immunostaining showed both MSH2 and MLH1 as positive), and segregation with disease in the family (the variant did not segregate with disease in the family). Together, these analyses suggest the variant does not contribute to tumorigenesis (Spaepen_2006). Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and likely benign (n=2) while an expert panel (InSiGHT), following a recent re-classification, cites the variant as uncertain significance (originally classified as likely benign in 2013) citing new tumour Likelihood Ratios: Multifactorial likelihood analysis posterior probabilty is in class 3. (0.091). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl RCV000662836 SCV000785694 likely benign Lynch syndrome I 2017-11-01 criteria provided, single submitter clinical testing
Color RCV000130283 SCV000903282 likely benign Hereditary cancer-predisposing syndrome 2016-10-06 criteria provided, single submitter clinical testing

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