Submissions for variant NM_000179.3(MSH6):c.3799_3800del (p.Met1267fs)

dbSNP: rs267608114

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074931	SCV000108144	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000491355	SCV000580237	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-31	criteria provided, single submitter	clinical testing	The c.3799_3800delAT pathogenic mutation, located in coding exon 8 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 3799 to 3800, causing a translational frameshift with a predicted alternate stop codon (p.M1267Gfs*7). This mutation has been detected in individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome, including an individual whose tumor demonstrated high microsatellite instability and loss of MSH6 by immunohistochemistry (IHC) (Nilbert M et al. Fam Cancer. 2009;8(1):75-83; Klarskov L et al. Am J Surg Pathol, 2011 Sep;35:1391-9). 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.
GeneDx	RCV000202066	SCV000617714	pathogenic	not provided	2017-06-02	criteria provided, single submitter	clinical testing	This deletion of two nucleotides in MSH6 is denoted c.3799_3800delAT at the cDNA level and p.Met1267GlyfsX7 (M1267GfsX7) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ACAT[delAT]GGTA. The deletion causes a frameshift which changes a Methionine to a Glycine at codon 1267, and creates a premature stop codon at position 7 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.3799_3800delAT has been reported in individuals with Lynch syndrome (Nilbert 2009, Klarskov 2011). We consider this variant to be pathogenic.
Invitae	RCV000703066	SCV000831947	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met1267Glyfs*7) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18566915, 21836479). ClinVar contains an entry for this variant (Variation ID: 89463). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003492402	SCV000919751	pathogenic	Hereditary nonpolyposis colon cancer	2023-12-21	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3799_3800delAT (p.Met1267GlyfsX7) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251216 control chromosomes (gnomAD). c.3799_3800delAT has been reported in the literature in at-least one individuals affected with Hereditary Nonpolyposis Colorectal Cancer (example: Nilbert_2009). The following publications have been ascertained in the context of this evaluation (PMID: , 18566915, 25255306). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202066	SCV001134443	pathogenic	not provided	2019-08-20	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Myriad Genetics, Inc.	RCV003450980	SCV004188331	pathogenic	Lynch syndrome 5	2023-08-25	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	RCV003466950	SCV004195776	pathogenic	Endometrial carcinoma	2023-05-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202066	SCV004243103	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202066	SCV000257279	likely pathogenic	not provided		no assertion criteria provided	research