ClinVar Genomic variation as it relates to human health

The MUTYH c.544G>T; p.Glu182Ter variant, also known as c.586G>T; p.Glu196Ter for transcript NM_001128425.1, is reported in the medical literature in at least one individual with suspected polyposis with an additional pathogenic variant. The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 406822) and only reported in 1 out of 246262 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Loss of function variants are a known pathogenic mechanism in MUTYH-associated polyposis (Nielsen 2011). Considering available information, this variant is classified as pathogenic. References: Eliason K et al. The potential for increased clinical sensitivity in genetic testing for polyposis colorectal cancer through the analysis of MYH mutations in North American patients. J Med Genet. 2005 Jan;42(1):95-6. Nielsen M et al. MUTYH-associated polyposis (MAP). Crit Rev Oncol Hematol. 2011 Jul;79(1):1-16.

This pathogenic variant is denoted MUTYH c.586G>T at the cDNA level and p.Glu196Ter (E196X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously reported as MUTYH Glu182Ter (E182X) using alternate nomenclature, has been reported in the compound heterozygous state with a known pathogenic MUTYH variant in an individual with a history suspicious for familial adenomatous polyposis and negative APC testing (Eliason 2005). We consider this variant to be pathogenic.

This variant, also known as E182X, changes 1 nucleotide in exon 8 of the MUTYH 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 with a co-variant in the same gene in an individual affected with familial adenomatous polyposis (PMID: 15635083). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 1/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

This sequence change creates a premature translational stop signal (p.Glu196*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). This variant is present in population databases (rs745921592, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 15635083). This variant is also known as E182X. ClinVar contains an entry for this variant (Variation ID: 406822). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

This variant, also known as E182X, changes 1 nucleotide in exon 8 of the MUTYH 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 with a co-variant in the same gene in an individual affected with familial adenomatous polyposis (PMID: 15635083). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 1/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

The p.Glu196X variant in MUTYH has been reported in one individual (compound heterozygous for a second pathogenic; G382D) during a screening (Eliason 2005 PMID: 15635083). It has also been identified in 0.001% (1/113756) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 406822). This nonsense variant leads to a premature termination codon at position 196, which is predicted to lead to a truncated or absent protein. Loss of function of the MUTYH gene is an established disease mechanism in autosomal recessive MAP. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive MAP. ACMG/AMP Criteria applied: PVS1, PM2.

The p.E196* pathogenic mutation (also known as c.586G>T), located in coding exon 8 of the MUTYH gene, results from a G to T substitution at nucleotide position 586. This changes the amino acid from a glutamic acid to a stop codon within coding exon 8. This alteration has been reported in a likely compound heterozygous state in one of 219 individuals found negative for APC mutations during clinical genetic testing for familial adenomatous polyposis (Eliason K et al. J. Med. Genet. 2005 Jan;42:95-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

The MUTYH p.Glu196X variant was identified in 1 of 1050 proband chromosomes (frequency: 0.0001) from individuals or families with FAP, in an anonymized North American study of patients at risk of FAP and HNPCC, who were negative for APC, MSH2 and MLH1 mutations (Eliason 2005). The variant was also identified by our laboratory in 1 individual with MAP. The variant was identified in the InSiGHT Colon Cancer Gene Variant Database-LOVD (by Eliason 2005) and not in dbSNP, Clinvitae database, COSMIC, ClinVar database, GeneInsight - COGR database, UMD databases, 1000 Genomes Project, Exome Variant Server project, or the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015). The p.Glu196X variant leads to a premature stop codon at position 196, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants in the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.