Submissions for variant NM_000179.3(MSH6):c.3142C>T (p.Gln1048Ter)

dbSNP: rs200492211

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000202056	SCV000149310	pathogenic	not provided	2018-06-20	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MSH6 c.3142C>T at the cDNA level and p.Gln1048Ter (Q1048X) at the protein level. The substitution creates a nonsense variant, changing a Glutamine to a premature stop codon (CAG>TAG). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one individual with colorectal cancer and one with endometrial cancer whose tumors showed loss of MSH6 via mismatch repair immunohistochemistry (Talseth-Palmer 2010, Buchanan 2014). Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics	RCV000490956	SCV000580150	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-27	criteria provided, single submitter	clinical testing	The p.Q1048* pathogenic mutation (also known as c.3142C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 3142. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This mutation has been reported in multiple individuals with personal and/or family histories of colorectal cancer, and tumor studies have shown microsatellite instability and/or loss of MSH6 protein by immunohistochemistry associated with this mutation (Talseth-Palmer BA et al. Hered Cancer Clin Pract, 2010 May;8:5; Ward RL et al. J. Clin. Oncol. 2013 Jul;31:2554-62; Buchanan DD et al. J. Clin. Oncol. 2014 Jan;32:90-100). 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	RCV000544323	SCV000624821	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-01-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 127580). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1048*) 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).
MGZ Medical Genetics Center	RCV002288592	SCV002578972	pathogenic	Lynch syndrome 5	2022-03-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288592	SCV004185589	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202056	SCV000257233	pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500240	SCV000592622	pathogenic	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 p.Gln1048X variant was identified in two individuals or families with Lynch syndrome related cancers (Buchanan 2014, Talseth-Palmer 2010); tumours from affected individuals with the variant were shown to be MSH6 deficient by immunohistochemistry. The variant was also identified in the HGMD and the ClinVar database (classified as a pathogenic variant by GeneDx). The p.Gln1048X variant leads to a premature stop codon at position 1048, which is predicted to lead to 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 this 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.