ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.565C>T (p.Arg189Cys) (rs587780748)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123152 SCV000166456 uncertain significance MYH-associated polyposis 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 203 of the MUTYH protein (p.Arg203Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587780748, ExAC 0.03%). This variant has been observed in individuals affected with colorectal cancer or multiple colorectal adenomas (PMID: 28135145, 27978560, 17949294). This variant is also known as c.565C>T (p.Arg189Cys) in the literature. ClinVar contains an entry for this variant (Variation ID: 135988). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C3). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 5
Ambry Genetics RCV000220980 SCV000273013 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-26 criteria provided, single submitter clinical testing The p.R203C variant (also known as c.607C>T), located in coding exon 8 of the MUTYH gene, results from a C to T substitution at nucleotide position 607. The arginine at codon 203 is replaced by cysteine, an amino acid with highly dissimilar properties. <span style="background-color:initial">This alteration was previously reported in an individual with greater than 5 colorectal adenomas; however, no other alterations in the MUTYH<span style="background-color:initial"> gene were detected and this alteration was classified as a variant of unknown significance (Olschwang S et al. Genet. Test<span style="background-color:initial">. 2007;11:315-20). This alteration has also been reported in 1/450 patients with colorectal cancer diagnosed under the age of 50 years who were tested with a multi-gene panel (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet., 2018 04;14:e1007352). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000123152 SCV000487326 uncertain significance MYH-associated polyposis 2015-12-22 criteria provided, single submitter clinical testing
GeneDx RCV000478528 SCV000565255 uncertain significance not provided 2018-05-14 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.607C>T at the cDNA level, p.Arg203Cys (R203C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant, also known as c.565C>T (p.Arg189Cys) using alternate nomenclature, was observed in the heterozygous state in an individual with multiple colorectal adenomas and in at least two individuals with colorectal cancer (Olschwang 2007, Pearlman 2017, Yurgelun 2017). MUTYH Arg203Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MUTYH Arg203Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two MUTYH pathogenic variants on opposite chromosomes.
Color Health, Inc RCV000220980 SCV000685649 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478528 SCV001134481 uncertain significance not provided 2018-09-24 criteria provided, single submitter clinical testing
Mendelics RCV000123152 SCV001135263 uncertain significance MYH-associated polyposis 2019-05-28 criteria provided, single submitter clinical testing

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