ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2635C>T (p.Gln879Ter) (rs63751469)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076530 SCV000107560 pathogenic Lynch syndrome I 2018-06-13 reviewed by expert panel curation This variant is before the cutoff (codon 888) and therefore Class 5
Ambry Genetics RCV000491055 SCV000580528 pathogenic Hereditary cancer-predisposing syndrome 2017-06-09 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000521246 SCV000617595 pathogenic not provided 2018-03-22 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2635C>T at the cDNA level and p.Gln879Ter (Q879X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA). This variant has been reported in a patient referred for Lynch syndrome testing (Baudhuin 2005). This variant is located in the Helix-turn-helix domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011, Wielders 2017) and is predicted to cause loss of normal protein function through protein truncation. Even though nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 56 amino acids are no longer translated. MSH2 c.2635C>T was not observed in large population cohorts (Lek 2016). Based on currently available evidence, we consider MSH2 c.2635C>T to be pathogenic.
Invitae RCV000697633 SCV000826255 pathogenic Hereditary nonpolyposis colon cancer 2019-10-14 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MSH2 gene (p.Gln879*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 56 amino acids of the MSH2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with suspected Lynch syndrome, but it was referred to as c.2637C>T in the literature (PMID: 15858146). ClinVar contains an entry for this variant (Variation ID: 91028). This variant is expected to disrupt nearly the entire C-terminal portion of the MSH6 and MSH3 interaction domains of the MSH2 protein, as well as the helix-turn-helix domain (PMID: 9774676, 18822302, 17531815). Although functional studies have not been done for this particular variant, loss of the C-terminal region of the protein likely impairs MSH2 function (PMID: 9774676, 18822302, 17531815). A different truncation (p.Leu888Cysfs*4) that lies downstream of this variant has been determined to be pathogenic (PMID: 9222765, 8640829). This suggests that deletion of this region of the MSH2 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

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