ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2246_2250del (p.Glu749fs)

dbSNP: rs1553369665
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567028 SCV000662337 pathogenic Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing The c.2246_2250delAATTG pathogenic mutation, located in coding exon 14 of the MSH2 gene, results from a deletion of 5 nucleotides at nucleotide positions 2246 to 2250, causing a translational frameshift with a predicted alternate stop codon (p.E749Gfs*36). 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 RCV001865719 SCV002236756 pathogenic Hereditary nonpolyposis colorectal neoplasms 2022-06-03 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 479849). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu749Glyfs*36) 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).
Myriad Genetics, Inc. RCV003451216 SCV004188957 pathogenic Lynch syndrome 1 2023-08-08 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
All of Us Research Program, National Institutes of Health RCV004000862 SCV004825780 pathogenic Lynch syndrome 2023-06-08 criteria provided, single submitter clinical testing This variant deletes 5 nucleotides in exon 14 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

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