ClinVar Genomic variation as it relates to human health

This duplication of four nucleotides in MSH6 is denoted c.3753_3756dupATTA at the cDNA level and p.Val1253IlefsX23 (V1253IfsX23) at the protein level. The normal sequence, with the bases that are duplicated in braces, is ATTC[ATTA]GTAG. The duplication causes a frameshift, which changes a Valine to an Isoleucine at codon 1253, and creates a premature stop codon at position 23 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 234794). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is present in population databases (rs754183111, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Val1253Ilefs*23) 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).

The c.3753_3756dupATTA pathogenic mutation, located in coding exon 8 of the MSH6 gene, results from a duplication of ATTA at nucleotide position 3753, causing a translational frameshift with a predicted alternate stop codon (p.V1253Ifs*23). 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.

The MSH6 c.3753_3756dup (p.Val1253Ilefs*23) variant (also known as c.3753_3756dupATTA, p.V1253IfsX23) alters the translational reading frame of the MSH6 mRNA and is predicted to cause the premature termination of MSH6 protein synthesis. The variant has not been reported in the published literature. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.

This variant inserts 4 nucleotides in exon 8 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. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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.

The MSH6 p.Val1253IlefsX23 variant was not identified in the literature nor was it identified in dbSNP, (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, Clinvitae database, COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database, “Zhejiang Colon Cancer Database”, the ClinVar database, GeneInsight COGR database, and UMD. The c.3753_3756dupATTA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1253 and leads to a premature stop codon 23 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.