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; Not observed at 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; Observed in multiple individuals with Lynch syndrome-associated cancers, including colon cancers which demonstrate absence of MSH6 protein by immunohistochemistry (Hendriks 2004, Nilbert 2009, Baglietto 2010, Sjursen 2010, Klarskov 2011, Okkels 2012, Therkildsen 2015, Yurgelun 2015, Young 2018); This variant is associated with the following publications: (PMID: 28460341, 15236168, 20587412, 18566915, 25648859, 25980754, 22495361, 25525159, 20028993, 19575290, 18415027, 26517685, 27013479, 21836479, 29945567, 32710294, 31297992, 30291343, 32832836, 32794656)

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.Arg482*) 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 (rs63750909, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 15236168, 20028993, 20587412, 21836479, 22495361). ClinVar contains an entry for this variant (Variation ID: 89194). For these reasons, this variant has been classified as Pathogenic.

This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a 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 (PMID: 15236168, 19575290, 20587412, 22495361, 28460341) and colorectal cancer (PMID: 20028993). This variant has been identified in 1/31384 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.R482* pathogenic mutation (also known as c.1444C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1444. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation was detected in a family that met Amsterdam II criteria and the mutation showed moderate segregation with disease (Hendriks YM et al. Gastroenterology 2004 Jul;127(1):17-25). The mutation has also been reported in multiple patients with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome, some of whom have been shown to have tumors with loss of MSH6 protein on immunohistochemistry (IHC) (Nilbert M et al. Fam. Cancer 2009 Jun;8(1):75-83; Jensen UB et al. Breast Cancer Res. Treat. 2010 Apr;120:777-82; Okkels H et al. Appl. Immunohistochem. Mol. Morphol. 2012 Oct;20:470-7). The p.R482* mutation was identified in a 34 year-old woman with choroid plexus carcinoma (CPC) that demonstrated absence of MSH6 protein by IHC (Zhu VW et al. Clin Neurol Neurosurg 2017 Jul;158:46-48). 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.

MSH6: PVS1, PP1, PS3:Supporting

ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated

Criteria applied: PVS1,PS4_MOD,PM2_SUP

This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a 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 (PMID: 15236168, 19575290, 20587412, 22495361, 28460341) and colorectal cancer (PMID: 20028993). This variant has been identified in 1/31384 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 MSH6 p.Arg482X variant was identified in 6 of 3135 proband chromosomes (frequency: 0.002) from individuals or families with CRC and prostate cancer (Hendriks 2004, Nilbert 2008, Dominguez-Valentin 2016). The variant was also identified in dbSNP (ID: rs63750909) as “With Pathogenic allele” ,ClinVar (5x, as pathogenic, by InSight, Invitae, GeneDx, Counsyl, Ambry Genetics), Clinvitae (3x, as pathogenic, by ClinVar and Clinvitae), Cosmic (as pathogenic), UMD-LSDB (8 records, as causal), Insight Colon Cancer Gene Variant Database (4x, as class 5, pathogenic), Mismatch Repair Genes Variant Database (2x as pathogenic), Insight Hereditary Tumors Database (5x , as class 5, "affects function”). The variant was not identified in MutDB, GeneInsight-COGR, Zhejiang Colon Cancer databases. The variant was identified in control databases in 1 of 30956 chromosomes at a frequency of 0.000032 in East Asian population (Genome Aggregation Consortium Feb 27, 2017). The p.Arg482X variant leads to a premature stop codon at position 482, which is predicted to lead to a truncated or absent protein and loss of function.4. Loss of function variants of the MSH6 gene are an established mechanism of disease in colorectal cancer 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.