ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2731C>T (p.Arg911Ter) (rs63751017)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074777 SCV000107987 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000129807 SCV000184618 pathogenic Hereditary cancer-predisposing syndrome 2019-03-18 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000202017 SCV000211301 pathogenic not provided 2018-12-17 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH6 c.2731C>T at the cDNA level and p.Arg911Ter (R911X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in several Lynch syndrome families (Goodfellow 2003, Buttin 2004, Plaschke 2004, Talseth-Palmer 2010, Egoavil 2013). MSH6 Arg911Ter has also been observed de novo, reported with a second MSH6 nonsense variant in a child with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome with absent MSH6 protein expression on IHC in both tumor and normal tissue (Galuppini 2018). We consider this variant to be pathogenic.
Invitae RCV000524149 SCV000261510 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg911*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in multiple individuals with Lynch syndrome (PMID: 12732731, 23047549, 23263490, 20487569, 15483016). ClinVar contains an entry for this variant (Variation ID: 89312). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000411710 SCV000487951 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2015-12-06 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074777 SCV000592613 pathogenic Lynch syndrome 2012-10-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202017 SCV000601541 pathogenic not provided 2016-09-08 criteria provided, single submitter clinical testing
Color RCV000129807 SCV000685320 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000074777 SCV000695825 pathogenic Lynch syndrome 2016-07-22 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.2731C>T (p.Arg911X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 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 (e.g. p.Arg1005X, p.Arg1068X, p.Phe1088fsX5, etc.). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/120692 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant was identified in patients from the literature, patients with various types of cancer and HNPCC families. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000411710 SCV000744293 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-05-31 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000411710 SCV000840013 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-11-26 criteria provided, single submitter clinical testing The c.2731C>T (p.Arg911*) variant in the MSH6 gene is predicted to introduce a premature translation stop codon. This variant has been reported in the literature in multiple individuals with ovarian, colorectal, or prostate cancer (PMID: 12732731, 23047549, 23263490, 15236168, 15483016, 25117503, 16885385). The c.2731C>T (p.Arg911*) variant in the MSH6 gene is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000202017 SCV000884139 pathogenic not provided 2017-09-08 criteria provided, single submitter clinical testing The MSH6 c.2731C>T; p.Arg911Ter variant (rs63751017) has previously been described in individuals and families with Lynch syndrome (Goodfellow 2003, Pal 2012, Plaschke 2004, Rosty 2014, Talseth-Palmer 2010). It is reported in the ClinVar database as pathogenic (Variation ID: 89312), and observed in the general population at a very low allele frequency of 0.008 percent (1/13006 alleles) in the Exome Variant Server, and 0.003 percent (1/30970 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript. Based on the above information, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Arg911Ter: Goodfellow PJ et al. Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proc Natl Acad Sci U S A. 2003 May 13;100(10):5908-13. Pal T et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012 Nov 6;107(10):1783-90. Plaschke J et al. Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. J Clin Oncol. 2004 Nov 15;22(22):4486-94. Rosty C et al. High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry. Fam Cancer. 2014 Dec;13(4):573-82. Talseth-Palmer BA et al. MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. Hered Cancer Clin Pract. 2010 May 21;8(1):5.
Fulgent Genetics,Fulgent Genetics RCV000763495 SCV000894281 pathogenic Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000074777 SCV000967753 pathogenic Lynch syndrome 2019-05-07 criteria provided, single submitter clinical testing The p.Arg911X variant in MSH6 has been reported in at least 13 individual with MSH6-associated cancers and segregated in at least 4 affected relatives (Goodfellow 2003, Buttin 2004, Hendriks 2004, Plaschke 2004, Hampel 2006, Talseth-Palmer 2010, Pal 2012, Palles 2013, Rosty 2014, Susswein 2015, Akbari 2017, Raskin 2017). This variant has also been reported in ClinVar (Variation ID 89312) and has been identified in 1/15426 European chromosomes by gnomAD ( This nonsense variant leads to a premature termination codon at position 911, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1; PS4; PP1; PM2.
CSER _CC_NCGL, University of Washington RCV000148645 SCV000190360 pathogenic Endometrial carcinoma 2014-06-01 no assertion criteria provided research
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202017 SCV000257227 pathogenic not provided no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000411710 SCV000734216 pathogenic Hereditary nonpolyposis colorectal cancer type 5 no assertion criteria provided clinical testing

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