Submissions for variant NM_000179.3(MSH6):c.694C>T (p.Gln232Ter)

dbSNP: rs587779318

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075025	SCV000108246	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000412800	SCV000490619	pathogenic	not provided	2016-06-09	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MSH6 c.694C>T at the cDNA level and p.Gln232Ter (Q232X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant was reported in a recent study (Pritchard 2012) and is considered pathogenic.
Invitae	RCV001383732	SCV001582985	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln232*) 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: 22658618). ClinVar contains an entry for this variant (Variation ID: 89556). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002362703	SCV002662249	pathogenic	Hereditary cancer-predisposing syndrome	2017-02-21	criteria provided, single submitter	clinical testing	The p.Q232* pathogenic mutation (also known as c.694C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 694. This changes the amino acid from a glutamine to a stop codon within coding exon 4. 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.
Revvity Omics, Revvity	RCV000412800	SCV003833099	likely pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003450991	SCV004188251	pathogenic	Lynch syndrome 5	2023-08-10	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.
Baylor Genetics	RCV003460700	SCV004195817	pathogenic	Endometrial carcinoma	2023-04-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000412800	SCV000592575	uncertain significance	not provided		no assertion criteria provided	clinical testing	The p.Gln232X variant has been reported in the literature in 1/120 proband chromosomes of an individual with Lynch syndrome (Pritchard 2012); it was not identified in any of the 38 control chromosomes. In addition, it has been previously identified in one family by our laboratory meeting MOH criteria for FAP. The variant was also identified in the InSiGHT Colon Cancer database. The variant leads to a premature stop codon at position 232 which is predicted to cause premature truncation or absent protein product and loss of function. Loss of function is an established disease mechanism for the MSH6 gene and is the type of variant expected to cause Lynch syndrome. In summary, based on the above information, this variant is classified as pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000412800	SCV001932243	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000412800	SCV001955648	pathogenic	not provided		no assertion criteria provided	clinical testing