ClinVar Genomic variation as it relates to human health

Coding sequence variation resulting in a stop codon

This variant deletes 4 nucleotides 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 families affected with Lynch syndrome (PMID: 18566915, 20028993) and in individuals affected with ovarian cancer, endometrial cancer or colorectal cancer (PMID: 10537275, 22006311, 23047549). This variant has been identified in 2/250930 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.

This frameshift variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. The frequency of this variant in the general population, 0.000008 (2/250930 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33471991 (2021)), ovarian cancer (PMID: 30322717 (2018), 29348823 (2017), 24728189 (2014)), and Lynch syndrome associated cancers (PMID: 31054147 (2019), 29345684 (2018), 28944238 (2017), 26845104 (2016)). Based on the available information, this variant is classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Val717Alafs*18) 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 (rs587782275, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and associated cancers (PMID: 10537275, 18566915, 20028993, 22006311, 23047549, 23652311). ClinVar contains an entry for this variant (Variation ID: 89256). For these reasons, this variant has been classified as Pathogenic.

The c.2150_2153delTCAG pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of 4 nucleotides at nucleotide positions 2150 to 2153, causing a translational frameshift with a predicted alternate stop codon (p.V717Afs*18). This mutation has been detected in multiple hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome patients, several with tumors demonstrating microsatellite instability and/or loss of MSH6 protein on immunohistochemistry (Baglietto L et al. J Natl Cancer Inst, 2010 Feb;102:193-201; Talseth-Palmer BA et al. Hered Cancer Clin Pract, 2010 May;8:5; Walsh T et al. Proc Natl Acad Sci U S A, 2011 Nov;108:18032-7; van Lier MG et al. J Pathol, 2012 Apr;226:764-74; Pagin A et al. Br J Cancer, 2013 May;108:2079-87; Shirts BH et al. Genet Med, 2016 10;18:974-81; Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575; Roberts ME et al. Genet Med, 2018 10;20:1167-1174; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Dow E et al. Intern Med J, 2018 Nov;48:1325-1330; Tian W et al. Int J Cancer, 2019 09;145:1290-1298). This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439), and was reported in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). 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: The MSH6 c.2150_2153delTCAG (p.Val717Alafs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 1/121546 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). However, ExAC indicates that the location is a low-quality site, therefore, this observation needs to be cautiously considered. Multiple publications cite the variant in affected individuals including one family (Talseth-Palmer_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

The MSH6 c.2150_2153delTCAG; p.Val717AlafsTer18 variant (rs267608058), also known as c.2147_2150delCAGT or 2149delTCAG, is reported in the literature in multiple individuals affected with Lynch syndrome and associated cancers (Baglietto 2010, DeRycke 2017, Hirasawa 2017, Kolodner 1999, Nilbert 2009, Pal 2012, Sun 2017, Talseth-Palmer 2010, Walsh 2011). This variant is also reported in ClinVar (Variation ID: 89256). It is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several downstream truncating variants have been described in individuals with various cancers and are considered pathogenic (Nilbert 2009, Pal 2012). Based on available information, this variant is considered to be pathogenic. References: Baglietto L et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010 Feb 3;102(3):193-201. PMID: 20028993 DeRycke MS et al. Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. Mol Genet Genomic Med. 2017 Jul 23;5(5):553-569. PMID: 28944238 Hirasawa A et al. Prevalence of pathogenic germline variants detected by multigene sequencing in unselected Japanese patients with ovarian cancer. Oncotarget. 2017 Nov 28;8(68):112258-112267. PMID: 29348823 Kolodner RD et al. Germ-line msh6 mutations in colorectal cancer families. Cancer Res. 1999 Oct 15;59(20):5068-74. PMID: 10537275 Nilbert M et al. Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. Fam Cancer. 2009;8(1):75-83. PMID: 18566915 Pal T et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012 Nov 6;107(10):1783-90. PMID: 23047549 Sun J et al. Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. PMID: 28724667 Talseth-Palmer BA et al. MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. Hered Cancer Clin Pract. 2010 May 21;8(1):5. PMID: 20487569 Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. PMID: 22006311

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 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; Reported in several individuals with colorectal, ovarian, and/or endometrial cancer, including multiple individuals with concordant tumor studies (Kolodner et al., 1999; Talseth-Palmer et al., 2010; Walsh et al., 2011; van Lier et al., 2012; Pagin et al., 2013); This variant is associated with the following publications: (PMID: 24763289, 22081473, 20487569, 23047549, 24728189, 18566915, 26845104, 22006311, 28724667, 28944238, 22658618, 29348823, 23652311, 30322717, 31054147, 32719484, 30787465, 33087929, 27535533, 35449176, 29922827, 28888541, 33511262, 33471991, 10537275)

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

The p.Val717AlafsX18 variant in MSH6 has been reported in 1 individual with endometrial cancer, 2 individuals with ovarian cancer, 3 individuals with colorectal cancer and 1 individual with Lynch syndrome (Walsh 2011, Baglietto 2010, Nilbert 2009, Pal 2012, Pagin 2013, Kolodner 1999, Hirasawa 2017). It has also been identified in 1/30612 of South Asian and in 1/34584 of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89256). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 717 and leads to a premature termination codon 18 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, the p.Val717AlafsX18 variant meets criteria to be classified as pathogenic for Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2, PS4_Moderate.

This variant has been identified by standard clinical testing. female patient with ovarian cancer Selected ACMG criteria: Pathogenic (I):PP5;PM2;PVS1

This variant deletes 4 nucleotides 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 families affected with Lynch syndrome (PMID: 18566915, 20028993) and in individuals affected with ovarian cancer, endometrial cancer or colorectal cancer (PMID: 10537275, 22006311, 23047549). Tumor data from an individual affected with ovarian and endometrial cancer demonstrated high microsatellite instability and loss of MSH6 protein expression, while another individual affected with early-onset colorectal cancer had tumor testing showing loss of MSH6 protein expression but low microsatellite instability (PMID: 23652311). This variant has been identified in 2/250930 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 p.Val717AlafsX18 deletion variant has been previously reported in the literature in 4 of 5340 proband chromosomes in individuals with either Lynch syndrome, colorectal cancer, endometriod or ovarian cancer, and it was absent from 378 control chromosomes (Kolodner 1999, Walsh 2011, Pal 2012, Nilbert 2008). The p.Val717AlafsX18 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 717 and leads to a premature stop codon 18 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 for Lynch syndrome. In summary, based on the above information, this variant meets our criteria to be classified as pathogenic.