Submissions for variant NM_001048174.2(MUTYH):c.205C>T (p.Arg69Ter)

gnomAD frequency: 0.00004  dbSNP: rs138775799

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129018	SCV000172918	pathogenic	Hereditary cancer-predisposing syndrome	2024-04-03	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) (Sieber OM et al. N. Engl. J. Med. 2003 Feb;348(9):791-9; Vogt S et al. Gastroenterology. 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	2022-05-03	criteria provided, single submitter	clinical testing	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; Published functional studies demonstrate a damaging effect: impaired glycosylase activity (Goto 2010); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19032956, 16134146, 12606733, 19793053, 17949294, 16557584, 18301448, 19732775, 25525159, 20848659, 23605219, 20618354, 19394335, 19414147, 19725997, 21235684, 30604180, 31589614, 32029870, 30787465)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471769	SCV000545773	pathogenic	Familial adenomatous polyposis 2	2024-01-28	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. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). This variant is present in population databases (rs138775799, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and/or MUTYH-associated polyposis (PMID: 12606733, 17949294, 19732775, 19793053, 20618354). This variant is also known as R83X and R69X. ClinVar contains an entry for this variant (Variation ID: 140827). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235267	SCV000601644	pathogenic	not provided	2017-03-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129018	SCV000911727	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 3 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 as homozygous in an individual affected with polyposis and colorectal cancer (PMID: 19793053; referred to as R83X in this article) and as compound heterozygous with a known pathogenic variant p.Tyr179Cys in an individual affected with polyposis (PMID: 20618354). This variant has been identified in 4/282870 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.
Illumina Laboratory Services, Illumina	RCV000471769	SCV000915419	pathogenic	Familial adenomatous polyposis 2	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	Familial adenomatous polyposis 2	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.
MGZ Medical Genetics Center	RCV000471769	SCV002578895	pathogenic	Familial adenomatous polyposis 2	2022-03-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000471769	SCV004198817	pathogenic	Familial adenomatous polyposis 2	2024-01-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000471769	SCV004837976	pathogenic	Familial adenomatous polyposis 2	2023-10-02	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 3 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 as homozygous in an individual affected with polyposis and colorectal cancer (PMID: 19793053; referred to as R83X in this article) and as compound heterozygous with a known pathogenic variant p.Tyr179Cys in an individual affected with polyposis (PMID: 20618354). This variant has been identified in 4/282870 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000471769	SCV004847998	pathogenic	Familial adenomatous polyposis 2	2016-06-13	criteria provided, single submitter	clinical testing	The p.Arg94X (also known as p.Arg97X or p.Arg83X) variant in MUTYH has been previously reported as compound heterozygous in one individual with MUTYH-related attenuated familial adenomatous polyposis (FAP); as heterozygous in one individual with FAP; and as double heterozygous with a disease causing MSH6 variant in one individual with HNPCC (Seiber 2003, Steinke 2008, Vogt 2009). It has also been identified in 2/16512 of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://-exac.broadinstitute.org; dbSNP rs138775799). This frequency is low enough to be consistent with the frequency of MUTYH-related attenuated FAP in the general population. This nonsense variant leads to a premature termination codon at position 94, which is predicted to lead to a truncated or absent protein. Homozygous loss of function of the MUTYH gene is an established disease mechanism in individuals with MUTYH-related attenuated FAP. In vitro functional studies provide some evidence that the p.Arg94X variant may impact protein function (Goto 2010). In summary, this variant meets our criteria to be classified as pathogenic for MUTYH-related attenuated FAP in an autosomal recessive manner based on the predicted impact of the variant.