ClinVar Genomic variation as it relates to human health

Coding sequence variation resulting in a stop codon

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; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Wijnen 1999, Plaschke 2004, Stormorken 2005, Oeverbeek 2007, Ramsoekh 2008, van Puijenbroek 2008, Sjursen 2010, Leenan 2012, van Lier 2012, Song 2014, DeRycke 2017, Xu 2020); Not observed at a 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: 25525159, 15236168, 18625694, 18301448, 22081473, 10508506, 23741719, 25345868, 25318681, 18415027, 15483016, 20587412, 17453009, 24728189, 22306203, 22274719, 16034045, 24145353, 20028993, 28514183, 24362816, 33194656, 28944238, 30013564, 30787465)

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

This sequence change creates a premature translational stop signal (p.Ser156*) 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 (rs63749873, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and rectal cancer and ovarian cancer (PMID: 10508506, 15483016, 16034045, 17453009, 18301448, 18625694, 22081473, 24728189). It is commonly reported in individuals of Dutch ancestry (PMID: 10508506, 15483016, 16034045, 17453009, 18301448, 18625694, 22081473, 24728189). ClinVar contains an entry for this variant (Variation ID: 89534). For these reasons, this variant has been classified as Pathogenic.

The p.S156* pathogenic mutation (also known as c.467C>G), located in coding exon 3 of the MSH6 gene, results from a C to G substitution at nucleotide position 467. This changes the amino acid from a serine to a stop codon within coding exon 3. This alteration has been identified in multiple individuals meeting Amsterdam diagnostic criteria for Lynch syndrome (Wijnen et al. Nature Genetics. 1999. Vol 23. 142-144; Overbeek et al. British Journal of Cancer. 2007. 96,1605-1612; van Lier M et al. J Pathol. 2012 Apr;226(5):764-74). Affected individuals have been reported with isolated loss of MSH6 or loss of both MSH6 and MSH2 proteins on immunohistochemistry (Steinke et al. European Journal of Human Genetics. 2208.16,587-592; Stormorken A et al. J Clin Oncol. 2005 Jul 20;23(21):4705-12). This alteration was also identified with c.1316A>G in an individual diagnosed with constitutional mismatch repair deficiency (Tesch VK et al. Front Immunol, 2018 Jul;9:1506). 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.

Variant summary: MSH6 c.467C>G (p.Ser156X) 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 8e-06 in 251286 control chromosomes. c.467C>G has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Wijnen_1999, Steinke_2008, vanLier_2012, DeRycke_2017, Hu_2018, Tesch_2018). 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. The following publications have been ascertained in the context of this evaluation (PMID: 18301448, 10508506, 22081473, 28944238, 29922827, 30013564). ClinVar contains an entry for this variant (Variation ID: 89534). Based on the evidence outlined above, the variant was classified as pathogenic.

The MSH6 c.467C>G variant is predicted to result in premature protein termination (p.Ser156*). This variant has been reported in one individual with rectal cancer (Plaschke et al. 2004. PubMed ID: 15483016), one individual with Lynch Syndrome (Post. 2021. PubMed ID: 33693762), one individual with ovarian cancer (Song et al. 2014. PubMed ID: 24728189, sup table S1), and several individuals with colon cancer with evidence of microsatellite instability and negative MSH6 immunohistochemistry staining (see for example, Overbeek et al. 2007. PubMed ID: 17453009, Leenen et al. 2012. PubMed ID: 22306203). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been classified as pathogenic by a ClinVar expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/89534). Nonsense variants in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic.

The MSH6 p.Ser156X variant was identified in 15 of 6088 proband chromosomes (frequency: 0.002) from individuals or families with HNPCC (Wijnen 1999, Steinke 2008, van Lier 2012, Hendriks 2004, Plaschke 2004, Stormorken 2005, Overbeek 2007, Ramsoekh 2008). The variant was also identified in dbSNP (ID: rs63749873) “With Pathogenic allele”, HGMD (3X), “Mismatch Repair Genes Variant Database” (7X), InSiGHT Colon Cancer Gene Variant Database (16X as “Pathogenic”), and the ClinVar database (classified as a pathogenic variant by an expert panel). Tumours with this variant were also found to be MSI-H (van Lier 2012, Overbeek 2007). This variant was also determined by extended haplotype analysis to be a founder mutation of ancient origin in the Dutch population (Ramsoekh 2008). The p.Ser156X variant leads to a premature stop codon at position 156, which is predicted to lead to 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.