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

dbSNP: rs863225388

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491837	SCV000580484	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-19	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 (p.I418Vfs*3). This mutation has been detected in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome; several whose tumors demonstrated loss of MSH2 by immunohistochemistry (IHC) (Roth RM et al. Am J Clin Pathol. 2016 Jul;146(1):50-6; Adar T et al. Cancer. 2018 08;124(15):3145-3153; Gordon AS et al. Am J Hum Genet. 2019 09;105(3):526-533). 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.
Laboratory for Molecular Medicine, Mass General Brigham 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 Diagnostics, LLC DBA Color Health	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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV003454515	SCV004188059	pathogenic	Lynch syndrome 1	2023-08-01	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202139	SCV000257128	pathogenic	not provided		no assertion criteria provided	research