Submissions for variant NM_000251.3(MSH2):c.1189C>T (p.Gln397Ter)

dbSNP: rs63750611

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076055	SCV000107068	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing a premature termination codon
Invitae	RCV001385673	SCV001585618	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-17	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: 90559). This variant is also known as 1257C>T. This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 8880570, 15235030, 18772310). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln397*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816).
Ambry Genetics	RCV002336224	SCV002643902	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-02	criteria provided, single submitter	clinical testing	The p.Q397* pathogenic mutation (also known as c.1189C>T), located in coding exon 7 of the MSH2 gene, results from a C to T substitution at nucleotide position 1189. This changes the amino acid from a glutamine to a stop codon within coding exon 7. This alteration was identified in a Swiss family with nonpolyposis colorectal cancer (Kovac M et al. Fam Cancer, 2011 Sep;10:605-16). 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.	RCV003452805	SCV004188114	pathogenic	Lynch syndrome 1	2023-07-31	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353639	SCV000592490	pathogenic	not provided		no assertion criteria provided	clinical testing	The MSH2 p.Gln397X variant was identified in 4 of 314 proband chromosomes from individuals with Lynch sydrome, Muir-Torre syndrome, or sporadic breast cancer (Bujalkova 2008, Froggatt 1996, Mangold 2004, Murata 2002). The variant was also identified in dbSNP (ID: rs63750611), HGMD, UMD (4X), “Mismatch Repair Genes Variant Database”, and the “InSiGHT Colon Cancer Database”. The p.Gln397X variant leads to a premature stop codon at position 397, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In addition, three studies demonstrated microsatellite instability in tumour samples with the variant; of these one showed loss of heterozygosity of MSH2, while the two others showed very weak or no expression of MSH2 by immunohistochemistry (Bujalkova 2008, Mangold 2004, Murata 2002). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.