ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2064G>A (p.Met688Ile) (rs63750790)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165796 SCV000216543 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,Conflicting evidence
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000410248 SCV000267401 uncertain significance Lynch syndrome I 2016-03-18 criteria provided, single submitter reference population
Counsyl RCV000410248 SCV000488061 uncertain significance Lynch syndrome I 2015-12-28 criteria provided, single submitter clinical testing
Invitae RCV000524376 SCV000548225 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 688 of the MSH2 protein (p.Met688Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs63750790, ExAC 0.06%). This variant has been reported in individuals affected with colorectal and endometrial cancer, as well as in individuals with hereditary nonpolyposis colorectal cancer (PMID: 9559627, 10777691, 14499697, 23741719). It has also been observed in three control individuals in a healthy cohort of 179 individuals (PMID: 15527911). ClinVar contains an entry for this variant (Variation ID: 90875). Functional studies do not agree on the effect of this variant on mismatch repair activity (PMID: 17720936, 22739024, 21309037). A different missense substitution at this codon (p.Met688Arg) has been determined to be pathogenic (PMID: 22739024, 10080150, 15075785, 20010080, 22739024, 21239990, 21225464). This suggests that the methionine residue is critical for MSH2 protein function and that other missense substitutions at this position may also be pathogenic. 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.
Color RCV000165796 SCV000685006 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing

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