Submissions for variant NM_000179.3(MSH6):c.3067G>T (p.Glu1023Ter)

dbSNP: rs267608059

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074801	SCV000108012	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
University of Washington Department of Laboratory Medicine, University of Washington	RCV000074801	SCV000266094	pathogenic	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491450	SCV000580306	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-17	criteria provided, single submitter	clinical testing	The p.E1023* pathogenic mutation (also known as c.3067G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 3067. This changes the amino acid from a glutamic acid to a stop codon within coding exon 4. This mutation has been reported in multiple families with Lynch syndrome associated cancers (Nilbert M et al. Fam Cancer, 2009 Jun;8:75-83; Klarskov L et al. Am J Surg Pathol, 2011 Sep;35:1391-9; Okkels H et al. Appl. Immunohistochem. Mol. Morphol., 2012 Oct;20:470-7; Shirts BH et al. Genet Med, 2016 10;18:974-81). 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	RCV000687014	SCV000814562	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-08-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89336). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and endometrial and breast cancer (PMID: 18566915, 21836479, 22495361, 26845104). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1023*) 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).
Myriad Genetics, Inc.	RCV003450956	SCV004185645	pathogenic	Lynch syndrome 5	2023-08-22	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000074801	SCV004847556	pathogenic	Lynch syndrome	2023-09-19	criteria provided, single submitter	clinical testing	The p.Glu1023X variant in MSH6 has been reported in 2 individuals with Lynch syndrome associated cancers, including colorectal cancer and endometrial cancer and segregated with disease in 1 affected relative. Tumors sampled from 1 individual lacked MSH6 expression by immunohistochemistry (IHC), whereas the tumor from the affected relative showed normal MSH6 by IHC (Nilbert 2009 PMID: 18566915, Klarskov 2011 PMID: 21836479, Shirts 2016 PMID: 26845104). This variant was absent from large population studies (gnomAD v.3.1.2). This nonsense variant leads to a premature termination codon at position 1023, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. Additionally, this variant was classified as Pathogenic on Sep 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89336). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting, PS3_Supporting.