ClinVar Genomic variation as it relates to human health

Coding sequence variation resulting in a stop codon

Variant summary: MSH6 c.3847_3850dupATTA (p.Thr1284AsnfsX6) 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 250872 control chromosomes. c.3847_3850dupATTA has been reported in the literature in individuals affected with Lynch Syndrome (e.g. Nilbert_2009, Okkels_2012). These data indicate that the variant is likely to be associated with disease. 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.

This variant inserts 4 nucleotides in exon 9 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.3850_3851insATTA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome or colorectal cancer (PMID: 18566915, 20028993, 21836479, 22495361). 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.

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; 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 a personal or family history of Lynch syndrome or ovarian cancer (Nilbert et al., 2009; Okkels et al., 2012; Lilyquist et al., 2017); This variant is associated with the following publications: (PMID: 18566915, 22495361, 21836479, 28888541)

The c.3847_3850dup (p.Thr1284Asnfs*6) variant in the MSH6 gene is located on the exon 9 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Thr1284Asnfs*6), resulting in an absent or disrupted protein product. This variant has been reported in multiple unrelated individuals with Lynch syndrome-associated cancers (PMID: 22495361, 33693762, 32659967, 18566915, 28514183, 30383610). This variant is absent in the general population database (gnomAD). Loss-of-function variants of MSH6 are known to be pathogenic (PMID: 30376427, 18269114, 29345684). The variant is reported in ClinVar as pathogenic (ID: 89475) and reviewed by the expert panel. Therefore, the c.3847_3850dup (p.Thr1284Asnfs*6) variant of MSH6 has been classified as pathogenic.

The c.3847_3850dupATTA pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of ATTA at nucleotide position 3847, causing a translational frameshift with a predicted alternate stop codon (p.T1284Nfs*6). This mutation has been identified in families whose history is suggestive of HNPCC/Lynch syndrome (Nilbert M et al. Fam. Cancer. 2009 Jan:8(1):75-83; Klarskov L et al. Am. J. Surg. Pathol. 2011 Sep;35(9):1391-9). Immunohistochemistry staining has demonstrated both intact and absent MSH6 protein in colorectal tumors in individuals with this mutation (Okkels H et al. Appl. Immunohistochem. Mol. Morphol. 2012 Oct;20(5):470-7). Of note, this alteration is also designated as c.3850_3851insATTA in published literature. 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.

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

This sequence change creates a premature translational stop signal (p.Thr1284Asnfs*6) 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). 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 (PMID: 22495361). This variant is also known as c.3850_3851insATTA. ClinVar contains an entry for this variant (Variation ID: 89475). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.

The p.Thr1284fs variant in MSH6 has been reported in 1 individual with MSH6-associated cancers (Nilbert 2009) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1284 and leads to a premature termination codon 6 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. Furthermore, this variant was classified as Pathogenic on Sept. 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV000108157.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner.

The MSH6 p.Thr1284Asnfs*6 variant was identified in the literature, although the frequency of this variant in an affected population was not provided (Espenschied 2017). The variant was also identified in dbSNP (ID: rs866771359) as "With Pathogenic allele" and ClinVar (classified as pathogenic by Ambry Genetics and Invitae). The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). This variant was identified by our laboratory in at least one patient with MSH6-deficient endometrial cancer. The c.3847_3850dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1284 and leads to a premature stop codon at position 1289. This alteration is then predicted to result in 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 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.