ClinVar Genomic variation as it relates to human health

Coding sequence variation resulting in a stop codon

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 been reported in multiple families affected with Lynch syndrome and is considered to be a founder mutation in the Dutch population (PMID: 11709755, 25345868). This variant has been identified in 1/31412 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.

Nonsense 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 a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as MSH6 217insT, MSH6 650insT, and MSH6 651_652insT; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Wu 1999, Plaschke 2000, Wu 2001, Berends 2002, Berends 2003, Hendriks 2004, Domingo 2005, Kets 2006, Overbeek 2007, Ramsoekh 2008, Steinke 2008, Ou 2009, van der Post 2010); This variant is associated with the following publications: (PMID: 16636019, 15782118, 15483016, 10521294, 20591884, 11586295, 18301448, 14645426, 18521850, 17117178, 18625694, 15236168, 10699937, 11709755, 20028993, 17453009, 12373605, 21081928, 19156873, 31589614)

This sequence change creates a premature translational stop signal (p.Lys218*) 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 (rs63750955, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and Lynch syndrome (PMID: 2059188, 10521294, 17453009, 18625694, 20028993). This variant is also known as 217insT. ClinVar contains an entry for this variant (Variation ID: 8932). For these reasons, this variant has been classified as Pathogenic.

Variant summary: MSH6 c.651dupT (p.Lys218X) 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. The variant allele was found at a frequency of 1.3e-05 in 150984 control chromosomes (gnomAD v3.1 database, genomes dataset). c.651dupT has been reported in the literature in multiple individuals affected with colorectal cancer and other tumors that belong to the Lynch Syndrome tumor spectrum (e.g. Plaschke_2000, Hendricks_2004, Kets_2006, Carnevali_2021); in some of these cases the lack of MSH6 protein on immunohistochemistry and/or high microsatellite instability was also noted in the associated tumor samples. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other ClinVar submitters, have assessed the variant since 2014, and all have 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 termination codon and is predicted to result in premature protein truncation.

The c.651dupT pathogenic mutation (also known as p.K218*), located in coding exon 4 of the MSH6 gene, results from a duplication of T at nucleotide position 651. This changes the amino acid from a lysine to a stop codon within coding exon 4. In one study, this mutation was identified in three individuals with suspected HNPCC (Wu Y et al. Am J Hum Genet. 1999 Nov;65(5):1291-8). This mutation was also reported in an individual diagnosed with colon cancer at the age of 61, prostate cancer at the age of 67, and both ureter and bladder cancers at the age of 73. Immunohistochemistry (IHC) studies of the bladder tumor were reported to have absent MSH2 staining (van der Post RS et al. J Med Genet. 2010 Jul;47(7):464-70). Furthermore, this mutation has been identified in multiple other individuals with a clinical suspicion of Lynch syndrome and/or tumors exhibiting MSI-H and loss of MSH6 on IHC (Kets CM et al. Br. J. Cancer. 2006 Dec;95:1678-82; Steinke V et al. Eur. J. Hum. Genet. 2008 May;16(5):587-92; Ramsoekh D et al. Gut 2008 Nov;57(11):1539-44). 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.

PM2, PS4_moderate, PVS1

The MSH6 c.651dup (p.Lys218*) variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. This variant has been reported in the published literature in individuals/families suspect of or diagnosed with Lynch Syndrome (PMID: 10521294 (1999), 17453009 (2007), 18625694 (2008), and 20028993 (2010)). It has also been described in an individual with a gynecological cancer (PMID: 34519692 (2022)), an individual with cancer in the urothelial tissue, colon, ureter, and prostate (PMID: 20591884 (2010)). In a large scale breast cancer association study, this variant has been observed in a breast cancer case (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). Based on the available information, this variant is classified as pathogenic.

The MSH6 c.651dupT variant is predicted to result in premature protein termination (p.Lys218*). This variant has been reported in multiple individuals with Lynch syndrome (Wu et al. 1999. PubMed ID: 10521294; Hendriks et al. 2004. PubMed ID: 15236168; Steinke et al. 2008. PubMed ID: 18301448; Van der Post et al. 2010. PubMed ID: 20591884). This variant was also reported in a patient with autosomal recessive constitutional mismatch repair deficiency (CMMRD) syndrome who was heterozygous for both p.Lys218* and another MSH6 frameshift (c.3957dupA / p.Ala1320Serfs*4; Kroeze et al. 2022. PubMed ID: 34964038). The p.Lys218* variant is reported in 0.0065% 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/8932/). Nonsense variants in MSH6 are expected to be pathogenic. Taken together, the p.Lys218* variant is interpreted as pathogenic.