ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.247C>T (p.Arg83Ter) (rs138775799)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129018 SCV000172918 pathogenic Hereditary cancer-predisposing syndrome 2018-02-02 criteria provided, single submitter clinical testing The p.R97* pathogenic mutation (also known as c.289C>T), located in coding exon 3 of the MUTYH gene, results from a C to T substitution at nucleotide position 289. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation has been previously reported in individuals with MUTYH-associated polyposis (MAP) (<span style="background-color:initial">Sieber OM et al. N. Engl. J. Med<span style="background-color:initial">. 2003 Feb;348(9):791-9; <span style="background-color:initial">Vogt S et al. Gastroenterology.<span style="background-color:initial"> 2009 Dec;137(6):1976-85). Of note, this alteration is also designated as R83X and c.247C>T in published literature. 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.
GeneDx RCV000235267 SCV000293115 pathogenic not provided 2018-04-02 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.289C>T at the cDNA level and p.Arg97Ter (R97X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also known as c.247C>T (p.Arg83Ter) and c.205C>T (p.Arg69Ter) using alternate transcripts, has been reported in the compound heterozygous state in several individuals with autosomal recessive MUTYH-Associated Polyposis and in the heterozygous state in several individuals with colorectal cancer and polyps (Sieber 2003, Aretz 2006, Olschwang 2007, Vogt 2009, Morak 2010). In addition, a functional study demonstrated that MUTYH Arg97Ter is associated with severely impaired glycosylase activity (Goto 2010). We therefore consider this variant to be pathogenic.
Invitae RCV000471769 SCV000545773 pathogenic MYH-associated polyposis 2020-10-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg97*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs138775799, ExAC 0.01%). This variant has been reported as homozygous or compound heterozygous in individuals affected with MUTYH-associated polyposis (PMID: 19793053, 19732775, 20618354), and in heterozygous individuals affected with colorectal cancer (PMID: 12606733, 17949294). It also has been reported in an individual affected with Lynch syndrome who also carried a pathogenic MSH6 variant (PMID: 18301448). This variant is also known as R83X and R69X in the literature. ClinVar contains an entry for this variant (Variation ID: 140827). An experimental study has shown that this nonsense change severely impacts the DNA glycosylase activity of the MUTYH protein (PMID: 20848659). Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235267 SCV000601644 pathogenic not provided 2017-03-29 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129018 SCV000911727 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000471769 SCV000915419 pathogenic MYH-associated polyposis 2017-04-28 criteria provided, single submitter clinical testing The MUTYH c.247C>T (p.Arg83Ter) variant, also reported as c.289C>T (p.Arg97Ter), is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg83Ter variant has been reported in at least six studies in which it is found in at least six individuals with MYH-associated polyposis, including in two in a homozygous state, in two in a compound heterozygous state with a missense variant on the second allele, and in two in a heterozygous state with a second variant remaining undetected (Sieber et al. 2003; Aretz et al. 2006; Olschwang et al. 2007; Steinke et al. 2008; Filipe et al. 2009; Morak et al. 2010). One of the individuals who was heterozygous for the p.Arg83Ter variant also carried a known pathogenic variant in the MSH6 gene in a heterozygous state (Steinke et al. 2008). The p.Arg83Ter variant was absent from 446 control chromosomes but is reported at a frequency of 0.00023 in the African American population from the Exome Sequencing Project. This is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. In vitro functional studies demonstrated that the adenine DNA glycosylase activity of the p.Arg83Ter variant protein was similar to background levels and severely impaired compared to wild type (Goto et al. 2010). Based on the evidence from the literature and the potential impact of stop-gained variants, the p.Arg83Ter variant is classified as pathogenic for MYH-associated polyposis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000471769 SCV000919788 pathogenic MYH-associated polyposis 2017-11-09 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.289C>T (p.Arg97X) variant results in a premature termination codon, predicted to cause a truncated or absent MUTYH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/277650 control chromosomes at a frequency of 0.0000144, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). This variant has been reported in multiple affected individuals. Functional assay showed variant with extremely severely defective DNA glycosylase activity (Goto_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

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