Submissions for variant NM_000251.3(MSH2):c.34dup (p.Glu12fs)

dbSNP: rs63750614

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076570	SCV000107601	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000221149	SCV000276142	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-14	criteria provided, single submitter	clinical testing	The c.34dupG pathogenic mutation, located in coding exon 1 of the MSH2 gene, results from a duplication of G at nucleotide position 34, causing a translational frameshift with a predicted alternate stop codon (p.E12Gfs*70). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with MSH2-related disease (Ambry internal data). In one study, this mutation was detected in 3/36 colorectal cancer families tested (Colombino M et al. Ann. Oncol. 2003 Oct;14:1530-6). This mutation has also been reported in a male with Muir-Torre syndrome; he had multiple (>30) sebaceous adenomas and sebaceous carcinomas and family history of colon cancer in his father, brother, paternal uncles, and cousin (Landis MN et al. J. Am. Acad. Dermatol. 2011 Nov;65:1054-1058.e1). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as "c.34_35insG" in published literature. 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.
Invitae	RCV000554624	SCV000625418	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu12Glyfs*70) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer and Muir-Torre syndrome (PMID: 14504054, 21550136, 28514183). This variant is also known as 34_35insG. ClinVar contains an entry for this variant (Variation ID: 91068). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202253	SCV001470550	pathogenic	not provided	2019-09-17	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of MSH2 protein synthesis. In the published literature, this variant has been reported in individuals affected with colorectal cancer and Muir-Torre syndrome (PMID: 14504054 (2003), 15862756 (2005), 21550136 (2011)). Based on the available information, this variant has been classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298463	SCV002598590	pathogenic	Hereditary nonpolyposis colon cancer	2022-09-27	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.34dupG (p.Glu12GlyfsX70) 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. The variant was absent in 223170 control chromosomes. c.34dupG has been reported in the literature in individuals affected with Lynch Syndrome. These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003452934	SCV004187996	pathogenic	Lynch syndrome 1	2023-07-26	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003452934	SCV004196938	pathogenic	Lynch syndrome 1	2021-05-18	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202253	SCV000257186	pathogenic	not provided		no assertion criteria provided	research