ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2335dup (p.Met779fs) (rs63750149)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076459 SCV000107488 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
Ambry Genetics RCV000490902 SCV000580605 pathogenic Hereditary cancer-predisposing syndrome 2018-06-01 criteria provided, single submitter clinical testing The c.2335dupA pathogenic mutation, located in coding exon 14 of the MSH2 gene, results from a duplication of A at nucleotide position 2335, causing a translational frameshift with a predicted alternate stop codon (p.M779Nfs*8). This pathogenic mutation has been reported in a patient meeting Amsterdam criteria for HNPCC (Lin X et al. Dig. Dis. Sci. 1999 Mar;44:553-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000697514 SCV000826130 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Met779Asnfs*8) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Lynch syndrome (PMID: 10080150). This variant is also known as a single base insertion ATG XAATG, in the literature. ClinVar contains an entry for this variant (Variation ID: 90957). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000076459 SCV000917710 likely pathogenic Lynch syndrome 2018-04-26 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2335dupA (p.Met779AsnfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as likely pathogenic/pathogenic by our laboratory (eg. c.2460_2462delinsA (p.Val821fsX2), c.2466T>A (p.Cys822X), and c.2633_2634delAG (p.Glu878fsX3)). The variant was absent in 246228 control chromosomes (gnomAD). The variant, c.2335dupA, has been reported in the literature in an individual affected with Lynch Syndrome (Lin_1999). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic.
Color Health, Inc RCV000490902 SCV001359867 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing

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