ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3261dup (p.Phe1088fs) (rs267608078)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 23
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074831 SCV000108042 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078312 SCV000110155 pathogenic not provided 2014-01-24 criteria provided, single submitter clinical testing
GeneDx RCV000078312 SCV000149321 pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing Frameshift 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 Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Hampel 2008, Sjursen 2010, Terui 2013, Kumamoto 2015, Rubio 2016, Lee 2017, Suzuki 2017, Tian 2019) Observed in the homozygous and compound heterozygous state in patients with constitutional mismatch repair deficiency in published literature (Ilencikova 2011, Ling 2018) Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database Not observed at a significant frequency in large population cohorts (Lek et al., 2016) This variant is associated with the following publications: (PMID: 32068069, 32029870, 32658311, 32832836, 31447099, 32060697, 18809606, 20587412, 24100870, 26249337, 27398995, 28523262, 28258479, 31054147, 30147880, 21674763, 29945567, 31297992, 19526325, 30322717, 23757202, 28481244, 28514183, 28332257, 28502729, 26681312, 24068316, 26318770, 27978560, 27446556, 25980754, 24689082, 9307272, 25117503, 28724667, 28944238, 28491141, 28195393, 20028993, 20045164, 25194673, 25110875, 26845104, 17117178, 12658575, 15837969, 18301448, 9929971, 15365995, 15483016, 16807412, 17453009, 20487569)
Ambry Genetics RCV000115412 SCV000185790 pathogenic Hereditary cancer-predisposing syndrome 2018-07-17 criteria provided, single submitter clinical testing The c.3261dupC pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a duplication of C at nucleotide position 3261, causing a translational frameshift with a predicted alternate stop codon (p.F1088Lfs*5). This well-characterized mutation has been reported in multiple individuals and families with Lynch syndrome-associated cancers (Akiyama Y et al. Cancer Res. 1997 Sep;57:3920-3; Shin KH et al. J. Hum. Genet. 1999;44:18-21; Plaschke J et al. J. Clin. Oncol. 2004 Nov;22:4486-94; Barnetson RA et al. N. Engl. J. Med. 2006 Jun;354:2751-63; Kets CM et al. Br. J. Cancer. 2006 Dec;95:1678-82; Overbeek LI et al. Br. J. Cancer. 2007 May;96:1605-12; Talseth-Palmer BA et al. Hered. Cancer Clin. Pract. 2010 May;8:5; Sjursen W et al. J. Med. Genet. 2010 Sep;47:579-85; Rosty C et al. Fam. Cancer. 2014 Dec;13:573-82; Liccardo R et al. Int. J. Mol. Sci. 2017 May;18:5). 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 RCV000524166 SCV000255263 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe1088Leufs*5) 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 reported in individuals with Lynch syndrome (PMID: 9307272, 12658575, 15483016, 17117178, 17453009, 18301448, 26318770), colorectal cancer (PMID: 16807412, 9929971, 24100870, 24689082), prostate cancer (PMID: 25117503), and endometrial cancer (PMID: 15837969). ClinVar contains an entry for this variant (Variation ID: 89364). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 24362816, 18269114). For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000074831 SCV000266095 pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Counsyl RCV000410401 SCV000489547 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2016-10-26 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115412 SCV000690338 pathogenic Hereditary cancer-predisposing syndrome 2021-02-02 criteria provided, single submitter clinical testing This variant inserts 1 nucleotide in exon 5 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in individuals and families affected with Lynch syndrome-associated cancer (PMID: 9307272, 9929971, 12658575, 15837969, 16807412, 17117178, 18301448, 24068316, 24100870, 25117503, 25110875, 25980754, 26681312, 28481244) and prostate and breast cancer (PMID: 25117503, 26681312). This variant also has been detected in homozygous and compound heterozygous carriers affected with constitutional mismatch repair deficiency syndrome (PMID: 21674763, 24068316). This variant has been identified in 17/280876 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000074831 SCV000695854 likely pathogenic Lynch syndrome 2016-08-01 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3261dupC (p.Phe1088Leufs) variant is located in exon 5 and 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. The variant of interest was observed in a large, broad control population, ExAC, with an allele frequency of 211/120336 (1/570), which is approximately 12 times the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7031. The high prevalence of the variant in controls can be explained by possibility of sequencing error, although the low penetrance is possibility too. The reason for low penetrance could be the existence of alternative splice acceptor site 7bp downstream of duplicated base, which can result in alternative protein lacking 32 amino acids. The variant of interest has been reported in multiple affected individuals with varying phenotypes, Lynch syndrome, atypical HNPCC, HNPCC (fulfilling either Bethesda or Amsterdam criteria), along with a family that had three homozygous children diagnosed with constitutional mismatch repair deficiency syndrome. In addition, one family (Palmer_2010) did indicate a lack of co-segregation with disease, along with another study, Yurgelun_2015 indicating the variant to have co-occurred with another pathogenic STK11 variant, c.375-1C>T. While other publications did indicate the variant segregated with disease (Akiyama_1997 and Ollikinen_2005). Furthermore, multiple reputable databases/clinical laboratories and publications cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000074831 SCV000711433 pathogenic Lynch syndrome 2019-04-22 criteria provided, single submitter clinical testing The p.Phe1088LeufsX5 variant in MSH6 has been reported in > 20 individuals with MSH6-associated cancers and segregated with disease in >3 affected relatives from 2 families (Akiyama 1997, Plaschke 2004, Ollikainen 2005, Barnetson 2006, Kets 2006, Overbeek 2007 , Steinke 2008, Sjursen 2010 , Bonadona 2011, Terui 2013, Hansen 2014, Rosty 2014, Susswein 2015). Tumors sampled from some of these individuals lacked MSH6 expression (Ollikainen 2005, Sjursen 2010, Terui 2013, Rosty 2014). Additionally, this variant has been reported in the compound heterozygous state in 1 individual with constitutional mismatch repair deficiency (CMMRD) and family history of MSH6-associated cancers (Bougeard 2014, Lavoine 2015). This variant has also been identified in 8/127394 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1088 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in Lynch syndrome. In addition, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108042.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PP1_Supporting, PS4, PM2_Supporting, PVS1.
GeneKor MSA RCV000115412 SCV000821740 pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This variation is an insertion of 1 nucleotide in exon 5 of the MSH6 mRNA (c.3261dupC), causing a frameshift at codon 1088. This creates a premature translation stop signal 5 amino acid residues later- p.(Phe1088Leufs*5) and is expected to result in an absent or disrupted protein product. Truncating variants in MSH6 are known to be pathogenic. This mutation has been reported in the literature in individuals with Lynch syndrome, colorectal, endometrial and prostate cancer (PMID: 9307272, PMID: 15483016, PMID: 26318770, PMID: 16807412, PMID: 24100870, (PMID: 25117503 PMID: 15837969). The mutation database ClinVar contains entries for this variant (Variation ID: 89364/).
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000410401 SCV000840011 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-07-31 criteria provided, single submitter clinical testing This c.3261dupC variant has been reported in multiple individuals with Lynch Syndrome (PMID9929971, 15483016, 26318770), 3 additional patients with colon cancer (PMID17117178, 16807412, 24100870) and 5 more patients with endometrial cancer including 3 from the same family showing co-segregation from one generation to the next (PMID1711717, PMID17453009, PMID15837969). This variant is predicted to cause a frameshift and, and create a premature stop codon. Based upon the above evidence, this c.3261_3262insC variant in the MSH6 gene is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078312 SCV000888268 pathogenic not provided 2020-01-10 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Mendelics RCV000410401 SCV001135836 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078312 SCV001250451 pathogenic not provided 2017-07-01 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV000410401 SCV001424780 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2019-03-04 criteria provided, single submitter clinical testing The c.3261dupC variant is a known pathogenic variant in the MSH6 gene. This variant results in the substitution of a leucine for a phenylalanine at codon 1088 and a premature stop codon five residues downstream. The MSH6 c.3261dupC variant has been reported in a number of individuals with Lynch syndrome-associated cancers (Sjursen 2010, Terui 2013, McCarthy 2018). In addition, this variant has been reported in the homozygous state in three children from a consanguineous family that all had constitutional mismatch repair deficiency (Ilencikova 2011). Therefore, we interpret c.3261dupC as a pathogenic variant.
Johns Hopkins Genomics, Johns Hopkins University RCV000410401 SCV001425317 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2020-04-29 criteria provided, single submitter clinical testing The MSH6 gene encodes a component of the DNA mismatch repair (MMR) system. The c.3261dupC variant in MSH6 has been reported in multiple individuals with Lynch Syndrome, an inherited condition that increases the risk of colorectal, endometrial and other cancers. It results in a premature stop codon in exon 5 likely leading to nonsense-mediated decay and lack of protein production. This variant is rare in a large population database (17/280876 total alleles, 0.0061%, no homozygotes) and has been reported in ClinVar. We consider this variant to be pathogenic.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000078312 SCV001450264 pathogenic not provided 2014-12-12 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000078312 SCV001480052 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000078312 SCV000257248 pathogenic not provided no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074831 SCV000592631 pathogenic Lynch syndrome no assertion criteria provided clinical testing The MSH6 p.Phe1088LeufsX5 duplication variant was identified in 6 of 4432 proband chromosomes (frequency: 0.001) from individuals with suspected Lynch syndrome (phenotype of colorectal or endometrial cancer) (Kets 2006, Ollikainen 2005, Plaschke 2004). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1088 and leads to a premature stop codon 4 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function of the MSH6 gene is an established disease mechanism in Lynch Syndrome. The p.Phe1088LeufsX5 variant was shown to co-segregate with late-onset endometrial cancer in one family, with 6 members affected across 3 generations (Ollikainen 2005). In addition, the tumours from three individuals in this family, and the tumours from three other individuals positive for this variant (Kets 2006, Plaschke 2004) were deficient for MSH6 protein by IHC. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic.
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249970 SCV001423984 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000078312 SCV001905889 pathogenic not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.