ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.697C>T (p.Arg233Ter) (rs587782885)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132522 SCV000187619 pathogenic Hereditary cancer-predisposing syndrome 2019-02-08 criteria provided, single submitter clinical testing The p.R247* pathogenic mutation (also known as c.739C>T) located in coding exon 9 of the MUTYH gene, results from a C to T substitution at nucleotide position 739. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been reported previously in multiple Dutch individuals with a diagnosis of MUTYH-associated polyposis (Nielsen M et al. J. Med. Genet. 2005 Sep;42:e54; Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85.e1-10; Nielsen M et al. Gastroenterology. 2009 Feb;136:471-6; Nielsen M et al. BMC Cancer. 2009 Jun;9:184; van der Post RS et al. Virchows Arch. 2009 Jan;454:25-9). This alteration is also referred to as c.697C>T and p.R233X in the 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 RCV000236829 SCV000292768 pathogenic not provided 2019-10-18 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; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as c.697C>T and R233X; This variant is associated with the following publications: (PMID: 19527492, 30604180, 28152038, 19732775, 19031083, 16140997, 19725997, 19394335, 19032956, 25525159)
Counsyl RCV000500909 SCV000797054 pathogenic MYH-associated polyposis 2018-01-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132522 SCV000905861 pathogenic Hereditary cancer-predisposing syndrome 2020-08-11 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 9 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 in individuals affected with MUTYH-associated polyposis and/or colorectal cancer (PMID: 19732775, 19031083, 16140997, http://www.insight-database.org/). This variant has been identified in 1/249816 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.
Invitae RCV000500909 SCV000957992 pathogenic MYH-associated polyposis 2020-10-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg247*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with MUTYH-associated polyposis (PMID: 19732775, 16140997). This variant is also known as p.Arg233X in the literature. ClinVar contains an entry for this variant (Variation ID: 143003). Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). For these reasons, this variant has been classified as Pathogenic.
Pathway Genomics RCV000144630 SCV000189957 likely pathogenic Carcinoma of colon 2014-07-24 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000144630 SCV000592697 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The p.Arg247X variant is reported in the literature in 2 of 88 proband chromosomes of individuals with colorectal carcinomas from MUTYH-associated polyposis (MAP) families, both of whom were compound heterozygous for this variant, consistent with the autosomal recessive inheritance of MAP. However, no controls were tested to establish the frequency of the variant in the general population (Nielsen_2009). The variant leads to a premature stop codon at position 247 which is predicted to cause premature truncation of the protein product. This is a loss of function DNA variant and loss of function is an established disease mechanism for the MUTYH gene. In summary, based on the above information, this variant is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000236829 SCV001741005 pathogenic not provided no assertion criteria provided clinical testing

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