ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1251_1268delinsAGTT (p.Ile418fs) (rs863225388)

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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 RCV000491837 SCV000580484 pathogenic Hereditary cancer-predisposing syndrome 2016-03-09 criteria provided, single submitter clinical testing The c.1251_1268del18insAGTT pathogenic mutation, located in coding exon 7 of the MSH2 gene, results from the deletion of 18 nucleotides and insertion of 4 nucleotides causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000615809 SCV000712553 pathogenic Lynch syndrome 2016-11-18 criteria provided, single submitter clinical testing The p.Ile418Valfs variant in MSH2 has not been previously reported in individual s with Lynch Syndrome or in large population studies, though the ability of thes e studies to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 418 and leads to a premature termination codon 3 amino acids downstr eam. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH2 gene is an established disease mechan ism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manne r based upon the predicted impact to the protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000615809 SCV000919709 likely pathogenic Lynch syndrome 2018-06-21 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1251_1268delinsAGTT (p.Ile418ValfsX3) 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 pathogenic by our laboratory (eg. c.1477C>T, p.Gln493X; c.1576delA, p.Thr526fsX17; c.1705_1706delGA, p.Glu569fsX2). The variant was absent in 246126 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1251_1268delinsAGTT in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Color Health, Inc RCV000491837 SCV001736330 pathogenic Hereditary cancer-predisposing syndrome 2020-10-05 criteria provided, single submitter clinical testing This variant affects 18 nucleotides, causing a frameshift, in exon 7 of the MSH2 gene. The variant creates a premature translational stop signal and is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer and/or polyps (PMID: 31422818). 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 ( Based on the available evidence, this variant is classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000202139 SCV000257128 pathogenic not provided no assertion criteria provided research

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