ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2545del (p.Leu849fs)

dbSNP: rs587779149
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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) RCV000076499 SCV000107528 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
Invitae RCV001854330 SCV002223166 pathogenic Hereditary nonpolyposis colorectal neoplasms 2021-07-08 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MSH2 protein in which other variant(s) (p.Leu888Cysfs*4) have been determined to be pathogenic (PMID: 8640829, 9222765, 9774676, 17531815, 18822302, 21879275). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 90997). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu849Trpfs*43) in the MSH2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 86 amino acid(s) of the MSH2 protein.
Ambry Genetics RCV002426637 SCV002742906 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-08 criteria provided, single submitter clinical testing The c.2545delC variant, located in coding exon 15 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 2545, causing a translational frameshift with a predicted alternate stop codon (p.L849Wfs*43). This variant has been identified as somatic in conjunction with a germline pathogenic MSH2 variant in a tumor that demonstrated high microsatellite instability with loss of MSH2/MSH6 expression by immunohistochemistry (Ambry internal data). This alteration occurs at the 3' terminus of theMSH2 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 9% of the protein. The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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