ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.733C>T (p.Arg245Cys) (rs200495564)

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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 RCV000129829 SCV000184645 pathogenic Hereditary cancer-predisposing syndrome 2018-03-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,Deficient protein function by in vitro/ex vivo assay,2 of classification of c (below) met (2c = 1b),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes)
Biesecker Lab/Human Development 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.
Color RCV000129829 SCV000685666 pathogenic Hereditary cancer-predisposing syndrome 2017-02-24 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000034678 SCV000592695 likely pathogenic MYH-associated polyposis 2015-08-05 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America RCV000587849 SCV000697708 pathogenic MUTYH-associated polyposis 2017-07-06 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.733C>T (p.Arg245Cys) variant involves the alteration of a conserved nucleotide, resulting in a missense change in the DNA glycosylase and Helix-turn-helix, base-excision DNA repair, C-terminal domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC and literature cohorts at a frequency of 0.0000836 (10/119638 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). The variant has been identified in homozygous patients with adenomatous polyposis (Miyaki_Mut Res_2005; Olschwang_Genetic Testing_2007) and in compound heterozygosity with a known pathogenic mutation (p.Gly396Asp). Functional studies indicate that the variant completely abolishes DNA glycosylase activity, mildly diminishes RNA and protein expression (Ruggieri_Oncogene_2013), and partially impairs base excision repair activity (Komine_HM_2015). Additionally, several variants at the 245 residue are reported in patients (p.Arg245Cys, p.Arg245His, and p.Arg245Leu), suggesting the residue is a mutational hotspot and is critical to function. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000034678 SCV000285964 pathogenic MYH-associated polyposis 2018-06-08 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.
Snyder Lab, Genetics Department,Stanford University RCV000722047 SCV000853090 pathogenic Familial colorectal cancer 2017-01-01 criteria provided, single submitter research

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