ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2035_2036del (p.Ile679fs)

dbSNP: rs587779129
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076367 SCV000107393 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
Invitae RCV001854323 SCV002230945 pathogenic Hereditary nonpolyposis colorectal neoplasms 2021-10-28 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 16405554). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile679Serfs*19) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816).
Ambry Genetics RCV002415561 SCV002723008 pathogenic Hereditary cancer-predisposing syndrome 2022-06-20 criteria provided, single submitter clinical testing The c.2035_2036delAT pathogenic mutation, located in coding exon 13 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 2035 to 2036, causing a translational frameshift with a predicted alternate stop codon (p.I679Sfs*19). This alteration has been previously identified in one individual of Japanese descent who had personal history of bladder and rectal cancer in addition to a liposarcoma, diagnosed at ages 31, 32, and 40, respectively. Analysis of the rectal and liposarcoma tumors using immunohistochemistry revealed loss of MSH2 protein (Hirata K et al. Am. J. Gastroenterol., 2006 Jan;101:193-6). 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.

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