Submissions for variant NM_000251.3(MSH2):c.1384C>T (p.Gln462Ter)

dbSNP: rs876657701

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000220084	SCV000271400	pathogenic	Lynch syndrome	2015-10-27	criteria provided, single submitter	clinical testing	The p.Gln462X variant in MSH2 has not been previously reported in individuals wi th Lynch syndrome but has been reported in ClinVar by another clinical laborator y (Variation ID 228365). This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 462, wh ich is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH2 gene is an established mechanism of disease for Lynch synd rome. In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon the on the predicted impact of the variant and its absence from controls.
Ambry Genetics	RCV000492035	SCV000580407	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-30	criteria provided, single submitter	clinical testing	The p.Q462* pathogenic mutation (also known as c.1384C>T), located in coding exon 8 of the MSH2 gene, results from a C to T substitution at nucleotide position 1384. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This mutation has been previously reported in a 52-year-old woman with family history of early onset colon, pancreatic, and endometrial cancers who was diagnosed with Lynch syndrome after having a sebaceous adenoma, which was found to have absent expression of MSH2 on immunohistochemistry (IHC), and a pheochromocytoma, which was also found to have absent expression of MSH2 and MSH6 on IHC as well as high microsatellite instability (Riff BP et al. Pancreas. 2015 May;44:676-8). 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	RCV000630030	SCV000750986	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln462*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 25872134). ClinVar contains an entry for this variant (Variation ID: 228365). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264489	SCV001442666	likely pathogenic	Hereditary nonpolyposis colon cancer	2020-10-01	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1384C>T (p.Gln462X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250098 control chromosomes (gnomAD). c.1384C>T has been reported in the literature in individuals affected with Lynch Syndrome and Muir-Torre, a variant of HNPCC (Hereditary Nonpolyposis Colorectal Cancer) (Dewey_2016, Riff_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003454595	SCV004187995	pathogenic	Lynch syndrome 1	2023-08-01	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.