ClinVar Miner

Submissions for variant NM_012222.2(MUTYH):c.724C>T (p.Arg242Cys) (rs200495564)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129829 SCV000184645 pathogenic Hereditary cancer-predisposing syndrome 2019-04-05 criteria provided, single submitter clinical testing ​The p.R245C pathogenic mutation (also known as c.733C>T), located in coding exon 9 of the MUTYH gene, results from a C to T substitution at nucleotide position 733. The arginine at codon 245 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been detected in the homozygous state in both Japanese and Portuguese APC mutation-negative adenomatous polyposis patients (Miyaki M et al. Mutat. Res. 2005 Oct 15;578(1-2):430-3; Olschwang S et al. Genet Test. 2007 Fall;11(3):315-20). This alteration was also seen in conjunction with a second MUTYH mutation in a 37 yo female with a history of colon cancer and approximately 50 colon polyps (Ruggieri V et al. Oncogene, 2013 Sep;32:4500-8). Current evidence supports codon 245 as a functionally important mutation hotspot, with multiple other missense alterations having been described as pathogenic or deficient in critical protein function in the literature (Aceto G et al. Hum Mutat. 2005 Oct;26(4):394; Vogt S et al. Gastroenterology. 2009 Dec;137(6):1976-85.e1-10; Bai H et al. Cancer Lett. 2007 May 18;250(1):74-81). In addition, a functional assay showed that p.R245C, which exists in a highly conserved and catalytic domain, results in partially defective protein expression levels compared to wild-type (Komine K et al. Hum. Mutat., 2015 Jul;36:704-11). Of note, this mutation is also described as p.R231C in published literature. This alteration has been detected in conjunction with a second pathogenic MUTYH mutation in an adenomatous polyposis patient without any detectable APC mutation (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as a pathogenic mutation.
Invitae RCV000034678 SCV000285964 pathogenic MYH-associated polyposis 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 245 of the MUTYH protein (p.Arg245Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs200495564, ExAC 0.03%). This variant has been reported as homozygous or compound heterozygous with another pathogenic variant in several individuals with MUTYH-associated polyposis and familial adenomatous polyposis (PMID: 15890374, 23108399, 17949294). This variant is also known as c.691C>T (p.Arg231Cys) in the literature. ClinVar contains an entry for this variant (Variation ID: 41761). Experimental studies have shown that this missense change disrupts MUTYH protein function (PMID: 23108399, 25820570). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000482239 SCV000565259 pathogenic not provided 2017-05-30 criteria provided, single submitter clinical testing This pathogenic variant is denoted MUTYH c.733C>T at the cDNA level, p.Arg245Cys (R245C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant, also reported as MUTYH c.691C>T (Arg231Cys), has been observed in the homozygous and compound heterozygous state in individuals with multiple polyps and colorectal cancer (Miyaki 2005, Olschwang 2007, Ruggieri 2013), and was observed in 1/481 individual with atherosclerosis, with no specific information about cancer history (Johnston 2012). In functional assays, MUTYH Arg245Cys was shown to abolish DNA glycosylase activity, decrease MUTYH transcript and protein expression levels and exhibited partially defective base excision repair when compared to wild-type, supporting pathogenicity (Ruggieri 2013, Komine 2015). MUTYH Arg245Cys was observed at an allele frequency of 0.035% (4/11526 alleles) in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MUTYH Arg245Cys occurs at a position that is conserved across species and is located within the FeS cluster domain (Ruggieri 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider this variant to be pathogenic.
Color Health, Inc RCV000129829 SCV000685666 pathogenic Hereditary cancer-predisposing syndrome 2020-02-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000034678 SCV000697708 pathogenic MYH-associated polyposis 2021-02-05 criteria provided, single submitter clinical testing Variant summary: MUTYH c.733C>T (p.Arg245Cys) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250436 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (5.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.733C>T has been reported in the literature in multiple individuals affected with adenomatous polyposis, either in homozygosity (Miyaki_2005, Olschwang_2007), or in compound heterozygosity with known- or likely pathogenic variants (Ruggieri_2013, Takao_2017, Furlan_2017). Functional studies indicated that the variant mildly diminishes RNA and protein expression, but completely abolishes DNA glycosylase activity (Ruggieri_2013), and partially impairs base excision repair (Komine_2015). Additionally, other variants at this amino acid position are reported in patients (p.Arg245His, p.Arg245Ser and p.Arg245Leu), suggesting this residue is critical for function. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=6) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Snyder Lab, Genetics Department,Stanford University RCV000722047 SCV000853090 pathogenic Familial colorectal cancer 2017-01-01 criteria provided, single submitter research
CeGaT Praxis fuer Humangenetik Tuebingen RCV000482239 SCV001248083 pathogenic not provided 2017-01-01 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034678 SCV000043376 probably pathogenic MYH-associated polyposis 2012-07-13 no assertion criteria provided research Converted during submission to Likely pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000482239 SCV000592695 uncertain significance not provided no assertion criteria provided clinical testing

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