ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2558A>C (p.Glu853Ala) (rs63750797)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164439 SCV000215079 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000164439 SCV000685056 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
Counsyl RCV000663223 SCV000786416 uncertain significance Lynch syndrome I 2018-05-01 criteria provided, single submitter clinical testing
GeneDx RCV000656884 SCV000565205 uncertain significance not provided 2017-11-28 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2558A>C at the cDNA level, p.Glu853Ala (E853A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAG>GCG). This variant was observed in a family with suspected Lynch syndrome, however the variant did not co-segregate with disease in the family (Kurzawski 2002, Kurzawski 2006). MSH2 Glu853Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Glu853Ala is located in the ATPase domain (Lutzen 2008, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available information, it is unclear whether MSH2 Glu853Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076501 SCV000107531 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000541354 SCV000625388 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 853 of the MSH2 protein (p.Glu853Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs63750797, ExAC 0.01%). This variant has been reported in the literature in a family with suspected hereditary non-polyposis colorectal cancer (HNPCC), but it did not segregate with disease (PMID: 11879922, 12362047, 16451135). ClinVar contains an entry for this variant (Variation ID: 90999). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000484878 SCV000691913 uncertain significance not specified no assertion criteria provided clinical testing
PreventionGenetics RCV000656884 SCV000806032 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing

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