ClinVar Genomic variation as it relates to human health

Coding sequence variation resulting in a stop codon

Variant summary: MSH6 c.3699_3702delAGAA (p.Lys1233AsnfsX6) 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 allele was found at a frequency of 4e-06 in 251238 control chromosomes. c.3699_3702delAGAA has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Goldberg_2014, Bonadona_2011, Batte_2014, Raymond_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 frameshift variant causes the premature termination of MSH6 protein synthesis. It has been reported in individuals with Lynch syndrome in the published literature (PMIDs: 25430799 (2015), 25980754 (2015), and 21642682 (2011)). Based on the available information, this variant is classified as pathogenic.

ACMG codes: PVS1, PS4M, PM2, PP5

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; This variant is associated with the following publications: (PMID: 25980754, 25213678, 27443514, 21642682, 25430799, 28152038, 18389388, 30787465, 29922827, 32719484, 28888541, 35366121)

This sequence change creates a premature translational stop signal (p.Lys1233Asnfs*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 present in population databases (rs267608115, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 18389388, 21642682). This variant is also known as c.3697_3700delAAAG. ClinVar contains an entry for this variant (Variation ID: 36593). For these reasons, this variant has been classified as Pathogenic.

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

PP4, PM2, PVS1

This variant deletes 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. This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 18389388, 21642682, 24933100, 27443514). This variant has been identified in 1/251238 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.

The c.3699_3702del variant in the MSH6 gene is located on the exon 8 and is predicted to shift the reading frame such that it introduces a premature translation termination codon (p.Lys1233Asnfs*6), resulting in an absent or disrupted protein product. This variant has been reported in multiple unrelated individuals with Lynch syndrome-related cancer (PMID: 25430799, 18389388, 28514183, 24933100, 25980754). Loss-of-function variants of MSH6 are known to be pathogenic (PMID: 30376427, 18269114, 29345684). The variant is reported in ClinVar as pathogenic (ID: 36593) and reviewed by the expert panel. The variant is rare in general population according to gnomAD (1/251238 chromosomes). Therefore, the c.3699_3702del (p.Lys1233Asnfs*6) variant in the MSH6 gene has been classified as pathogenic.

The c.3699_3702delAGAA (p.K1233Nfs*6) alteration, located in exon 8 (coding exon 8) of the MSH6 gene, consists of a deletion of 4 nucleotides from position 3699 to 3702, causing a translational frameshift with a predicted alternate stop codon after 6 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of <0.001% (1/251238) total alleles studied. The highest observed frequency was 0.001% (1/113596) of European (non-Finnish) alleles. This mutation has been reported in multiple families with Lynch syndrome (Bonadona, 2011). Based on the available evidence, this alteration is classified as pathogenic.

The MSH6 c.3699_3702delAGAA variant is predicted to result in a frameshift and premature protein termination (p.Lys1233Asnfs*6). This variant was reported in individuals with Lynch syndrome (examples, eTable 1. Bonadona V et al 2011. PubMed ID: 21642682; Goldberg Y et al 2014. PubMed ID: 25430799). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/36593/). Frameshift variants in MSH6 are considered pathogenic. This variant is interpreted as pathogenic.