MSH2 NM_000251.3:c.1147C>T, Arg383Ter

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Variant classification was performed using the VarSome platform (https://varsome.com/). The variant creates a premature termination codon. (PVS1) It also meet the criteria of PM2 and PP5 Assertion score is 17 according to PMID:32720330.

This sequence change creates a premature translational stop signal (p.Arg383*) 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, prostate cancer, and breast and/or ovarian cancer (PMID: 8592341, 15849733, 15872200, 23990280, 24344984, 24549055, 25117503, 25430799). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,627,235 individuals referred to our laboratory for MSH2 testing. ClinVar contains an entry for this variant (Variation ID: 90554). For these reasons, this variant has been classified as Pathogenic.

Variant summary: MSH2 c.1147C>T (p.Arg383X) 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 251460 control chromosomes. c.1147C>T has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome and associated tumors (example, Rossi_2017, Bonadona_2011, Banville_2006, Mangold_2005, Buerstedde_1995). These data indicate that the variant is very likely to be associated with disease. Banville et al (2006) showed loss of expression of MSH2 and MSH6 in tumor samples from a patient carrying this variant. Thompson et al (2014) reported a truncated polypeptide of MSH2 following protein truncation testing performed on patient RNA. Multiple clinical diagnostic laboratories and an expert panel (InSiGHT) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.R383* pathogenic mutation (also known as c.1147C>T), located in coding exon 7 of the MSH2 gene, results from a C to T substitution at nucleotide position 1147. This changes the amino acid from an arginine to a stop codon within coding exon 7. This variant has been detected in multiple HNPCC/Lynch syndrome families, and several had tumors demonstrating microsatellite instability and/or absence of MSH2 protein on immunohistochemistry (Buerstedde JM et al. J. Med. Genet., 1995 Nov;32:909-12; Heinimann K et al. Cancer, 1999 Jun;85:2512-8; Lamberti C et al. Gut, 1999 Jun;44:839-43; Lin X et al. Dig. Dis. Sci., 1999 Mar;44:553-9; Pistorius SR et al. Int J Colorectal Dis, 2000 Nov;15:255-63; Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Hampel H et al. N Engl J Med, 2005 May;352:1851-60; Mangold E et al. J Pathol, 2005 Dec;207:385-95; Spaepen M et al. Fam Cancer, 2006;5:179-89; South CD et al. J. Natl. Cancer Inst., 2008 Feb;100:277-81; Jasperson KW et al. Fam Cancer, 2010 Jun;9:99-107; Bonadona V et al. JAMA, 2011 Jun;305:2304-10; Buerki N et al. Genes Chromosomes Cancer, 2012 Jan;51:83-91; Dominguez-Valentin M et al. Hered Cancer Clin Pract, 2013 Dec;11:18; Rosty C et al. Fam. Cancer, 2014 Dec;13:573-82; Tzortzatos G et al. Hered Cancer Clin Pract, 2014;12:14; Goldberg Y et al. Fam Cancer, 2014 Mar;13:65-73; Xiong HY et al. Science, 2015 Jan;347:1254806; Goldberg Y et al. Clin Genet, 2015 Jun;87:549-53; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Tian W et al. Int J Cancer, 2019 09;145:1290-1298; Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199; Vietri MT et al. Med Oncol, 2021 Jan;38:13). This variant has also been identified in a cohort of high-risk breast/ovarian cancer patients (Castéra L et al. Eur J Hum Genet, 2014 Nov;22:1305-13). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.