Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
RCV000074710 | SCV000107917 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Coding sequence variation resulting in a stop codon |
Ambry Genetics | RCV000162397 | SCV000212720 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-05-12 | criteria provided, single submitter | clinical testing | The p.C687* pathogenic mutation (also known as c.2061T>A), located in coding exon 4 of the MSH6 gene, results from a T to A substitution at nucleotide position 2061. This changes the amino acid from a cystine to a stop codon within coding exon 4. In one study, this mutation was reported in an individual from Scotland who was diagnosed with colorectal cancer prior to 55 years of age (Baglietto L et al. J Natl Cancer Inst. 2010 Feb 3;102(3):193-201). 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. |
Gene |
RCV000201965 | SCV000490620 | pathogenic | not provided | 2017-10-26 | criteria provided, single submitter | clinical testing | This pathogenic variant is denoted MSH6 c.2061T>A at the cDNA level and p.Cys687Ter (C687X) atthe protein level. The substitution creates a nonsense variant, which changes a Cysteine to a premature stop codon(TGT>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 an individual with a tubular adenoma and in a Scottish familywith multiple cases of colorectal or Lynch syndrome cancers (Pino 2009, Baglietto 2010), and is consideredpathogenic. |
Invitae | RCV000530716 | SCV000624721 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-06-27 | criteria provided, single submitter | clinical testing | This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 19324997). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89246). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys687*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). |
Color Diagnostics, |
RCV000162397 | SCV000685252 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-07-26 | criteria provided, single submitter | clinical testing | This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: (19324997, 34039291). This variant has not been identified 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. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000201965 | SCV002047113 | pathogenic | not provided | 2021-05-18 | criteria provided, single submitter | clinical testing | This nonsense variant causes the premature termination of MSH6 protein synthesis. In addition, it has been reported in an individual with Lynch syndrome in the published literature (PMID: 19324997 (2009)). Based on the available information, this variant is classified as pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV002222379 | SCV002500505 | pathogenic | Hereditary nonpolyposis colon cancer | 2022-03-19 | criteria provided, single submitter | clinical testing | Variant summary: MSH6 c.2061T>A (p.Cys687X) 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 250560 control chromosomes. c.2061T>A has been reported in the literature in at-least two reports of individuals affected with Lynch Syndrome (example, Pino_2009, Baglietto_2010). Five 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. |
Myriad Genetics, |
RCV003450938 | SCV004187419 | pathogenic | Lynch syndrome 5 | 2023-08-16 | 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. |
Mayo Clinic Laboratories, |
RCV000201965 | SCV000257218 | likely pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Department of Pathology and Laboratory Medicine, |
RCV001353419 | SCV000592595 | pathogenic | Endometrial carcinoma | no assertion criteria provided | clinical testing | The p.Cys687X variant was not identified in the literature nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), COSMIC, Mismatch Repair Genes Variant, “MMR Gene Unclassified Variants, Zhejiang Colon Cancer, GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) databases. The variant was identified in dbSNP (ID: rs 267608068 “With Pathogenic allele”, in InSiGHT Colon Cancer Database (2x classified as pathogenic), in Clinvitae (2x classified as pathogenic), in LOVD as unknown. In the ClinVar database, the variant is classified as a pathogenic variant by InSIGHT and Ambry Genetics. The p.Cys687X variant leads to a premature stop codon at position 687, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this 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. |