ClinVar Genomic variation as it relates to human health

This sequence change creates a premature translational stop signal (p.Asn897Lysfs*3) 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-associated cancers (PMID: 20028993, 23047549; Invitae). This variant is also known as c.2690_2691insA. ClinVar contains an entry for this variant (Variation ID: 420121). For these reasons, this variant has been classified as Pathogenic.

The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data.

The c.2690dupA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of A at nucleotide position 2690, causing a translational frameshift with a predicted alternate stop codon (p.N897Kfs*3). This mutation has been identified in at least two individuals with Lynch syndrome-associated cancers (Baglietto L et al. J. Natl. Cancer Inst., 2010 Feb;102:193-201; Pal T et al. Br. J. Cancer, 2012 Nov;107:1783-90) and has also been identified in a proband with breast cancer ascertained via multigene panle testing (Gardner SA et al. Hered Cancer Clin Pract 2018 Jan;16:1). Of note, this alteration is also designated as c.2690_2691insA 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.

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 in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with personal or family history consistent with pathogenic variants in this gene (Baglietto 2010, Pal 2012); This variant is associated with the following publications: (PMID: 23047549, 20028993)

This variant inserts 1 nucleotide in exon 4 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 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.

Variant summary: MSH6 c.2690dupA (p.Asn897LysfsX3) 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 250556 control chromosomes (gnomAD). c.2690dupA has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Baglietto_2010) and ovarian cancer (e.g. Pal_2012). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

The MSH6 p.Asn897Lysfsx3 variant was identified in 1 of 3786 proband chromosomes (frequency: 0.0003) from individuals or families with epithelial ovarian cancer ascertained from three population-based studies and classified as pathogenic (Pal 2012). The variant was not identified in dbSNP, NHLBI Exome Sequencing Project, Exome Aggregation Consortium (March 14, 2015), COSMIC, MutDB, “Mismatch Repair Genes Variant ”, “MMR Gene Unclassified Variants”, “InSiGHT Colon Cancer”, “Zhejiang Colon Cancer”, the ClinVar, Clinvitae, GeneInsight COGR through the Canadian Open Genetics Repository and UMD Colon Cancer databases. The p.Asn897Lysfsx3 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 897 and leads to a premature stop codon 3 codons downstream. 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 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.