Submissions for variant NM_000179.3(MSH6):c.1806_1809del (p.Glu604fs)

dbSNP: rs63750735

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074687	SCV000107890	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000558537	SCV000624693	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-04-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu604Leufs*5) 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 4 synchronous colorectal cancers at age 16 years and colon cancer (PMID: 11470537, 18409202, 26805314). ClinVar contains an entry for this variant (Variation ID: 89224). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985827	SCV001134398	pathogenic	not provided	2019-06-04	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.
Mendelics	RCV000986718	SCV001135811	pathogenic	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408570	SCV002714919	pathogenic	Hereditary cancer-predisposing syndrome	2019-03-21	criteria provided, single submitter	clinical testing	The c.1806_1809delAAAG variant, located in coding exon 4 of the MSH6 gene, results from a deletion of 4 nucleotides at nucleotide positions 1806 to 1809, causing a translational frameshift with a predicted alternate stop codon (p.E604Lfs*5). This mutation has been reported in multiple individuals with colorectal cancer (Ohmiya N et al. Gene, 2001 Jul;272:301-13; Chika N et al. Jpn. J. Clin. Oncol., 2017 Feb;47:108-117). This mutation has also been reported in an individual with constitutional mismatch repair deficiency in a compound heterozygous state with another MSH6 mutation (Rahner N et al. Am. J. Med. Genet. A, 2008 May;146A:1314-9). 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.
Myriad Genetics, Inc.	RCV000986718	SCV004188226	pathogenic	Lynch syndrome 5	2023-08-15	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Color Diagnostics, LLC DBA Color Health	RCV002408570	SCV004357615	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-18	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant 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 individuals affected with Lynch syndrome or colorectal cancer (PMID: 18409202, 26805314, 27920101). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000074687	SCV004848292	pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Glu604LeufsX5 variant in MSH6 has been reported in 1 individual with colon cancer (Ohmiya 2001) and 1 individual with Lynch syndrome (Chika 2015), and segregated with disease in 1 affected relative (Chika 2015). It has also been reported in the compound heterozygous state in an individual with early onset colorectal cancer, vitiligo and systemic lupus erythrematosus (Rahner 2008). It was absent from large population studies. This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89224). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 604 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, the p.Glu604LeufsX5 variant meets criteria to be classified as pathogenic for Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2, PS4_supporting.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358609	SCV001554395	pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	The MSH6 p.Glu604Leufs*5 variant was identified in 1 of 64 proband chromosomes (frequency: 0.02) from individuals or families with colon cancer (Ohmiya 2001) and in one patient with systemic lupus erythematosus at age 16 and with colorectal cancer at age 17 (Rahner 2007). The variant was also identified in dbSNP (ID: rs63750735) as "With Pathogenic allele ", ClinVar (classified as pathogenic by InSight and Invitae), and in Insight Hereditary Tumors Database (2x). The variant was not identified in COGR, Cosmic, UMD-LSDB, Zhejiang University Database, or Mismatch Repair Genes Variant databases. 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.1806_1809del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 604 and leads to a premature stop codon at position 608. 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. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.