ClinVar Genomic variation as it relates to human health

Coding sequence variation introducing premature termination codon

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

Variant summary: MSH2 c.2152C>T (p.Gln718X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251584 control chromosomes (gnomAD). c.2152C>T has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Isidro_1999, Bonadona_2011, Valentin_2011, Monteiro Santos_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15222003, 21681552, 21642682, 24344984, 10612836, 22321913). ClinVar contains an entry for this variant (Variation ID: 90909). Based on the evidence outlined above, the variant was classified as pathogenic.

This variant changes 1 nucleotide in exon 13 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate

This sequence change creates a premature translational stop signal (p.Gln718*) 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: 10612836, 11910346, 15222003, 21681552, 26289772, 26437257). ClinVar contains an entry for this variant (Variation ID: 90909). For these reasons, this variant has been classified as Pathogenic.

The p.Q718* pathogenic mutation (also known as c.2152C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2152. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This mutation has been identified in multiple hereditary non-polyposis colorectal cancer (HNPCC)//Lynch syndrome families to date, most of them of Portuguese descent (Isidro G et al. Hum. Mutat., 2000 Jan;15:116; Lage PA et al. Cancer, 2004 Jul;101:172-7; Ewald J et al. Br J Surg, 2007 Aug;94:1020-7; Valentin MD et al. Fam. Cancer, 2011 Dec;10:641-7; Monteiro Santos EM et al. BMC Cancer, 2012 Feb;12:64; Rossi BM et al. BMC Cancer. 2017 Sep;17(1):623; Schneider NM et al. Cancer Med. 2018 May;7(5):2078-88). It has also been reported in three families with early-onset and/or familial prostate cancer, along with other more typical Lynch-associated tumors (Maia S et al. Fam. Cancer, 2016 Jan;15:111-21). Of note, this alteration is designated as p.Gln718* and p.Gln718Ter in published literature. 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.

The p.Gln718X variant has been previously reported in the literature in 10 of 416 proband chromosomes in individuals meeting various criteria for Lynch syndrome or early onset colorectal cancer (Ewald 2007, Isido 1999, Lage 2004, Terdiman 2002, Santos 2012) and an MSH2 deficient tumour was demonstrated by IHC for this variant in at least one study (Ewald 2007). The variant was also identified by the MMRV (memorial university database), and the InSight colorectal cancer database. The p.Gln718X variant leads to a premature stop codon at position 718, which is predicted to lead to a truncated or absent protein and loss of function. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease for Lynch syndrome. In summary, based on the above information, this variant is classified as pathogenic.