ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2801C>T (p.Thr934Met) (rs587779969)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212622 SCV000149433 uncertain significance not provided 2018-05-18 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2801C>T at the cDNA level, p.Thr934Met (T934M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has been observed in individuals with ovarian cancer, gastrointestinal stromal tumor, and breast cancer (South 2009, Ballinger 2016, Caminsky 2016). MSH2 Thr934Met was observed at an allele frequency of 0.014% (2/14,858) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located within the helix-turn-helix domain and in the region that interacts with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Thr934Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115524 SCV000187163 likely benign Hereditary cancer-predisposing syndrome 2018-06-28 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Other data supporting benign classification
Invitae RCV001086842 SCV000262352 likely benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000115524 SCV000690098 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-01 criteria provided, single submitter clinical testing
Mendelics RCV000986691 SCV001135766 likely benign Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194031 SCV001363267 uncertain significance not specified 2019-10-10 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2801C>T (p.Thr934Met) results in a non-conservative amino acid change in 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 5.7e-05 in 247562 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (5.7e-05 vs 0.00057), allowing no conclusion about variant significance. c.2801C>T has been reported in the literature in individuals affected with HBOC, colorectal cancer in addition to an individual referred for genetic testing (Caminsky_2016, Hampel_2018, Mu_2016, South_2009, Wu_2019). 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three classified as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

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