Submissions for variant NM_000251.3(MSH2):c.1165C>T (p.Arg389Ter)

dbSNP: rs587779075

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076052	SCV000107065	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing a premature termination codon
GeneDx	RCV000202008	SCV000149403	pathogenic	not provided	2024-03-13	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with personal and family histories consistent with pathogenic variants in this gene (PMID: 9052445, 10196371, 15849733, 19698169, 19459153, 21642682, 25559809); This variant is associated with the following publications: (PMID: 15235030, 25569433, 17453009, 9052445, 25117503, 22883484, 20215533, 10196371, 25525159, 25430799, 26681312, 25559809, 12658575, 27863258, 15849733, 27601186, 25648859, 28874130, 19698169, 11920650, 15713769, 21642682, 18566915, 30521064, 29933315, 31054147, 31857677, 31921681, 32489267, 32294063, 31615790, 31332305, 31742824, 34178123, 34148862, 31830689, 36073783, 33309985, 33939675, 19459153)
Ambry Genetics	RCV000115494	SCV000184319	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-19	criteria provided, single submitter	clinical testing	The p.R389* pathogenic mutation (also known as c.1165C>T), located in coding exon 7 of the MSH2 gene, results from a C to T substitution at nucleotide position 1165. This changes the amino acid from an arginine to a stop codon within coding exon 7. This alteration has been reported in multiple individuals from several populations meeting Amsterdam criteria, with features of Muir-Torre syndrome, or with Lynch-syndrome related tumors with absent MSH2 IHC expression and/or microsatellite instability (Mangold E et al. J. Med. Genet. 2004 Jul;41:567-72; Roupret M et al. J. Med. Genet. 2004 Jul;41(7):e91; Mongiat-Artus P et al. Virchows Arch. 2006 Aug;449:238-43; Skeldon SC et al. Eur. Urol. 2013 Feb;63:379-85; Rosty C et al. Fam. Cancer. 2014 Dec;13:573-82; Therkildsen C et al. Eur. J. Neurol. 2015 Apr;22:717-24; Goldberg Y et al. Clin. Genet. 2015 Jun;87:549-53). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524332	SCV000253796	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg389*) 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 cancers (PMID: 10196371, 15235030, 19459153, 21642682, 22883484, 25117503). 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 1,370,736 individuals referred to our laboratory for MSH2 testing. ClinVar contains an entry for this variant (Variation ID: 90557). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202008	SCV000257124	pathogenic	not provided	2023-07-06	criteria provided, single submitter	clinical testing	PP5, PM2_moderate, PS4_moderate, PVS1
Counsyl	RCV000409481	SCV000488244	pathogenic	Lynch syndrome 1	2016-02-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115494	SCV000537676	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-20	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 7 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 been reported in multiple individuals affected with Lynch syndrome (PMID: 21642682, 25117503, 25648859, 28874130) and in individuals affected with colorectal cancer, whose tumors showed the absence of MSH2 protein expression and microsatellite instability (PMID: 21868491, 22883484). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202008	SCV000601425	pathogenic	not provided	2023-06-07	criteria provided, single submitter	clinical testing	This variant causes the premature termination of MSH2 protein synthesis. In the published literature, this variant has been reported in individuals with Lynch syndrome associated cancers (PMID: 15235030 (2004), 15849733 (2005), 15855432 (2005), 15713769 (2005), 19459153 (2009), 22883484 (2013), 25117503 (2014), 26681312 (2015), 25648859 (2015), 25430799 (2015), 31054147 (2019)). In a large-scale breast cancer association study, the variant was observed in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Mendelics	RCV000076052	SCV000837828	pathogenic	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000076052	SCV000917712	pathogenic	Lynch syndrome	2018-07-13	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1165C>T (p.Arg389X) 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 (eg. c.1189C>T, p.Gln397X; c.1216C>T, p.Arg406X). The variant was absent in 246248 control chromosomes (gnomAD). The variant, c.1165C>T, has been reported in the literature in multiple individuals affected with Lynch Syndrome (Caldes_2002, Chong_2009, Pinol_2005, Casey_2005, Mangold_2005, Mongiat-Artus_2006, Wagner_2003). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001332303	SCV001524572	pathogenic	Mismatch repair cancer syndrome 1	2020-07-08	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	RCV000409481	SCV002106383	pathogenic	Lynch syndrome 1		criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115494	SCV002528817	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-29	criteria provided, single submitter	curation
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000409481	SCV002762822	pathogenic	Lynch syndrome 1	2022-12-09	criteria provided, single submitter	research	PVS1, PS4_STR, PM2_SUP
Myriad Genetics, Inc.	RCV000409481	SCV004018410	pathogenic	Lynch syndrome 1	2023-03-23	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	RCV000409481	SCV004196211	pathogenic	Lynch syndrome 1	2023-10-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000076052	SCV004827220	pathogenic	Lynch syndrome	2024-07-29	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 7 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 been reported in multiple individuals affected with Lynch syndrome (PMID: 21642682, 25117503, 25648859, 28874130) and in individuals affected with colorectal cancer, whose tumors showed the absence of MSH2 protein expression and microsatellite instability (PMID: 21868491, 22883484). 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV000409481	SCV005438892	pathogenic	Lynch syndrome 1	2023-07-22	criteria provided, single submitter	clinical testing	The observed stop gained c.1165C>Tp.Arg389Ter variant in MSH2 gene has been reported previously in heterozygous state in individuals affected with Lynch syndrome Liu et al., 2022. This variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss of function variants have been previously reported to be disease causing Thompson et al., 2014. Computational evidence MutationTaster - Disease causing automatic predicts damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000202008	SCV005877989	pathogenic	not provided	2024-03-31	criteria provided, single submitter	clinical testing	The MSH2 c.1165C>T; p.Arg389Ter variant (rs587779075, ClinVar Variation ID: 90557) is reported in individuals with Lynch syndrome associated cancers (Fujita 2022, Rossi 2017, Wischhusen 2020) and in ovarian cancer (Shao 2020). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Fujita M et al. Population-based Screening for Hereditary Colorectal Cancer Variants in Japan. Clin Gastroenterol Hepatol. 2022 Sep. PMID: 33309985. Rossi BM et al. A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. BMC Cancer. 2017 Sep 5. PMID: 28874130. Shao D et al. Prevalence of hereditary breast and ovarian cancer (HBOC) predisposition gene mutations among 882 HBOC high-risk Chinese individuals. Cancer Sci. 2020 Feb. PMID: 31742824. Wischhusen JW et al. Clinical Factors Associated with Urinary Tract Cancer in Individuals with Lynch Syndrome. Cancer Epidemiol Biomarkers Prev. 2020 Jan. PMID: 31615790.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353542	SCV000592489	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Arg389X variant was identified in 19 of 8326 proband chromosomes (frequency: 0.0023) from individuals or families with Lynch syndrome (Beck_1997_9052445, Caldes_2002_11920650, Casey_2005_15713769, Choi_2009_19698169, Mangold_2004_15235030, Mangold_2005_15849733, Millar_1999_10196371, Nilbert_2009_18566915, Overbeek_2007_17453009, Wagner_2003_12658575, Walsh_2010_20215533) as well as in one individual with prostate cancer (Rosty_2014_25117503) and one individual with urothelial cancer (Skeldon_2013_22883484). The variant was also identified in dbSNP (ID: rs587779075) as “With Pathogenic allele”, ClinVar (as pathogenic, reviewed by expert panel), Clinvitae (4x as pathogenic), Genesight-COGR (as pathogenic), Cosmic (as pathogenic, seen in colon cancer), UMD-LSDB (22x as causal), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (44x as causal). The variant was not identified in MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, MMR Gene Unclassified Variants Database. The variant was also identified by our laboratory in 4 individuals with colon cancer. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Nnn389X variant leads to a premature stop codon at position 389, 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 is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000202008	SCV002036646	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000202008	SCV002037401	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000409481	SCV002054075	not provided	Lynch syndrome 1		no assertion provided	literature only
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV002255278	SCV002526450	pathogenic	Mismatch repair cancer syndrome 2		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162491	SCV002758535	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004734626	SCV005362778	pathogenic	MSH2-related disorder	2024-06-21	no assertion criteria provided	clinical testing	The MSH2 c.1165C>T variant is predicted to result in premature protein termination (p.Arg389*). This variant has been reported in individuals with Lynch Syndrome and related cancers (Skeldon et al. 2013. PubMed ID: 22883484; Rosty et al. 2014. PubMed ID: 25117503; Susswein et al. 2016. PubMed ID: 26681312, Table S1; Rossi et al. 2017. PubMed ID: 28874130). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/90557/). Nonsense variants in MSH2 are expected to be pathogenic. This variant is interpreted as pathogenic.