ClinVar Genomic variation as it relates to human health

The MSH6 c.2230dupG (p.Glu744GlyfsTer12) variant, also reported as c.2228_2229insG, results in a frameshift, and is predicted to result in premature termination of the protein. The p.Glu744GlyfsTer12 variant has been reported in two studies and is found in a compound heterozygous state in two probands with colorectal cancer (Ward et al. 2013; DeRycke et al. 2017). The variant is reported at a frequency of 0.000016 in the European (non-Finnish) population from the Genome Aggregation Database but this is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of frameshift variants and evidence from literature, the p.Glu744GlyfsTer12 variant is classified as likely pathogenic for Lynch syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This sequence change creates a premature translational stop signal (p.Glu744Glyfs*12) 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 (rs773290953, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 23733757). ClinVar contains an entry for this variant (Variation ID: 183739). For these reasons, this variant has been classified as Pathogenic.

Variant summary: MSH6 c.2230dupG (p.Glu744GlyfsX12) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4e-06 in 250900 control chromosomes (gnomAD). c.2230dupG has been reported in the literature in individuals affected with colorectal cancer or ovarian and endometrial cancer with family histories of cancer (e.g. Ward_2013, Chan_2018). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23733757, 30093976). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This frameshift variant causes the premature termination of MSH6 protein synthesis. In addition, this variant has been reported in the literature in individuals with personal and family history of colorectal cancer (PMID: 28944238 (2017), 23733757 (2013)). Based on the available information, this variant is classified as pathogenic.

The MSH6 c.2230dup; p.Glu744GlyfsTer12 variant (rs786201050) is reported in the literature in several individuals affected with Lynch syndrome-associated cancers (Brand 2018, Chan 2018, DeRycke 2017, Espenschied 2017, Lilyquist 2017, Ward 2013). This variant is reported in ClinVar (Variation ID: 183739) and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be likely pathogenic. References: Brand R et al. Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma. Cancer. 2018 Sep 1;124(17):3520-3527. PMID: 30067863. Chan GHJ et al. Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers. Oncotarget. 2018 Jul 17;9(55):30649-30660. PMID: 30093976. 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. Espenschied CR et al. Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. J Clin Oncol. 2017 Aug 1;35(22):2568-2575. PMID: 28514183. Lilyquist J et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. 2017 Nov;147(2):375-380. PMID: 28888541. Ward RL et al. Population-based molecular screening for Lynch syndrome: implications for personalized medicine. J Clin Oncol. 2013 Jul 10;31(20):2554-62. PMID: 23733757.

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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ovarian and endometrial cancer (PMID: 30093976), colorectal cancer (PMID: 23733757, 28944238), and breast cancer (PMID: 29345684). This variant has been identified in 2/282300 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and has been reported in a control sample (PMID: 30128536). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Observed in individuals with MSH6-related cancers (PMID: 23733757, 30067863, 30093976, 28888541, 36744932); 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23733757, 30067863, 30093976, 28944238, 32719484, 30787465, 29922827, 28888541, 28514183, 36744932)

The c.2230dupG pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of G at nucleotide position 2230, causing a translational frameshift with a predicted alternate stop codon (p.E744Gfs*12). This mutation has been reported in multiple Lynch syndrome individuals (Ward RL et al. J. Clin. Oncol. 2013 Jul;31:2554-62; Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Brand R et al. Cancer, 2018 09;124:3520-352; 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.

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

PP5, PM2, PS4_moderate, PVS1

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 individuals affected with ovarian and endometrial cancer (PMID: 30093976), colorectal cancer (PMID: 23733757, 28944238), pancreatic adenocarcinoma (PMID: 30067863 ), and breast cancer (PMID: 29345684). This variant has been identified in 2/282300 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and has been reported in a control sample (PMID: 30128536). 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.Glu744Glyfs*12 variant was identified in 2 of 2872 proband chromosomes (frequency: 0.0007) from individuals or families with endometrial, ovarian, or colorectal cancer (Chan 2018, Ward 2013). The variant was also identified in dbSNP (ID: rs786201050) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics and three other submitters), and UMD-LSDB (1x as causal). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). This variant was identified by our laboratory in a patient with MSH6-deficient endometrial cancer. The c.2230dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 744 and leads to a premature stop codon at position 755. 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 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.

The MSH6 c.2230dupG variant is predicted to result in a frameshift and premature protein termination (p.Glu744Glyfs*12). This variant has been reported in individuals with colorectal cancer, pancreatic ductal adenocarcinoma, and endometrium ovarian cancer (Ward et al 2013. PubMed ID: 23733757; Brand et al. 2018. PubMed ID: 30067863; Table 4, Chan et al. 2018. PubMed ID: 30093976). This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant is interpreted as likely pathogenic/pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/183739). Frameshift variants in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic.

Variant interpreted as Pathogenic and reported on 03-24-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.