Submissions for variant NM_000179.3(MSH6):c.3920_3927dup (p.Glu1310fs)

dbSNP: rs587779295

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074949	SCV000108164	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000657357	SCV000779089	pathogenic	not provided	2021-02-08	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in patients with Lynch-related cancers consistent with pathogenic variants in this gene (Sjursen 2016); This variant is associated with the following publications: (PMID: 27064304)
Invitae	RCV000692457	SCV000820282	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2018-07-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Leu1330Valfs*12) that lies downstream of this variant has been determined to be pathogenic (PMID: 14520694, 15236168, 16237223, 19851887, 21155762, 24440087). This suggests that deletion of this region of the MSH6 protein is causative of disease. This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 89481). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the MSH6 gene (p.Glu1310Ilefs*20). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acids of the MSH6 protein.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657357	SCV000889504	pathogenic	not provided	2018-07-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003352767	SCV004057490	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-21	criteria provided, single submitter	clinical testing	The c.3920_3927dupATCTCCCA variant, located in coding exon 9 of the MSH6 gene, results from a duplication of ATCTCCCA at nucleotide position 3920, causing a translational frameshift with a predicted alternate stop codon (p.E1310Ifs*20). This alteration occurs at the 3' terminus of theMSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 52 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003450982	SCV004185700	pathogenic	Lynch syndrome 5	2023-08-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000657357	SCV001550533	pathogenic	not provided		no assertion criteria provided	clinical testing	The MSH6 p.Glu1310Ilefs*20 variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (ID: rs587779296) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, GeneDx, and InSight), and Insight Hereditary Tumors Database (2x as class5). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.3920_3927dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1310 and leads to a premature stop codon at position 1329. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.