ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.553C>T (p.Arg185Trp) (rs750592289)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478161 SCV000567147 likely pathogenic not provided 2015-07-02 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.553C>T at the cDNA level, p.Arg185Trp (R185W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant, also published as c.511C>T and p.Arg171Trp using alternate numbering, has been reported in the heterozygous state in an individual with a history of colon cancer and colon polyps (Cattaneo 2007). Additionally, MUTYH Arg185Trp has been shown to severely affected the binding affinity to the 8-oxoG:A DNA substrate resulting in a significant deficiency in the DNA glycosylase activity (D'Agostino 2010, Molatore 2010). MUTYH Arg185Trp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MUTYH Arg185Trp occurs at a position that is conserved across species and is not located in a known functional domain (Ruggieri 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available information, we consider MUTYH Arg185Trp to be a likely pathogenic variant.Although this variant is considered expected pathogenic, a second mutation, as would be required for expression of the recessive condition MAP, was not detected in this individual. The possibility that this patient harbors a second disease-causing MUTYH mutation that is undetectable by this test cannot be excluded. While the possibility that these variants are benign cannot be excluded, it is a strong candidate for a pathogenic variant. Two pathogenic variants in this gene (one inherited from each parent) are indicative of MUTYH-associated polyposis (MAP), an autosomal recessive condition causing an increased risk for the development of colon cancer and colon polyps. The risk for colon cancer is estimated to be 43% at age 60 and 80% at age 70 (Jenkins 2006, Lubbe 2009). Most individuals with MAP develop between 10 and 100 colon polyps; however, some affected individuals may never develop polyps. Adenomas are the most common polyp type in MAP, but serrated polyps are seen as well (Boparai 2008, Sieber 2003). Duodenal polyps and gastric fundic gland polyps have been observed in a minority of individuals with MAP. The lifetime risk for duodenal cancer is estimated to be 4% and the risk for other extraintestinal cancers such as endometrial, ovarian, bladder, breast, and skin may be increased (Barnetson 2007, Vogt 2009). Although an increased risk for colon cancer, endometrial cancer, and breast cancer has been reported in carriers of a single MUTYH mutation (Jenkins 2006, Rennert 2012, Win 2011), there is conflicting data regarding such associations (Out 2012, Santonocito 2011).
Ambry Genetics RCV000562580 SCV000670141 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-25 criteria provided, single submitter clinical testing The p.R185W variant (also known as c.553C>T), located in coding exon 7 of the MUTYH gene, results from a C to T substitution at nucleotide position 553. The arginine at codon 185 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration is located in the highly conserved pseudo-HhH motif region located MUTYH catalytic domain. Of note, this alteration is also designated as p.R171W (c.511C>T) in some published literature. This alteration was first reported in a male patient with colon cancer at age 49 and 90-100 polyps (Cattaneo F et al Genet. Med. 2007 Dec; 9(12):836-41). One functional analysis of this alteration using human proteins from a bacterial system suggests this alteration results in severe reduction in binding affinity as well as reduced adenine removal activity compared to the wild-type protein (D'Agostino VG et al DNA Repair (Amst.). 2010 Jun; 9(6):700-7). An additional study in which this alteration was expressed in Mutyh-/- mouse defective cells showed dysfunctional Base Excision Repair and goes on to suggest that the mutant protein produced by this alteration revealed a more pronounced phenotype than the simple loss of the Mutyh protein, suggesting a sort of dominant-negative effect (Molatore S et al Hum. Mutat. 2010 Feb; 31(2):159-66). In addition, an alteration at the same codon has been reported in a compound heterozygous state in 60 year old female polyposis patient and was not observed in 200 chromosomes from Swiss control samples (Russell AM et al. Int. J. Cancer. 2006 Apr; 118(8):1937-400). This amino acid position is 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000478161 SCV000891830 likely pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000562580 SCV000913518 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-27 criteria provided, single submitter clinical testing
Invitae RCV000803247 SCV000943109 uncertain significance MYH-associated polyposis 2020-08-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 185 of the MUTYH protein (p.Arg185Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs750592289, ExAC 0.001%). This variant has been observed in an individual affected with polyposis and colorectal cancer (PMID: 18091433). ClinVar contains an entry for this variant (Variation ID: 419386). Experimental studies have shown that this missense change abolishes the glycosylase activity of the MUTYH protein (PMID: 20418187, 19953527, 22252118). 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.
Center of Medical Genetics and Primary Health Care RCV001004834 SCV000987256 uncertain significance Familial cancer of breast 2020-07-15 no assertion criteria provided research ACMG Guidelines 2015 criteria The MUTYH gene variant p.Arg185Trp is in exon 7 and in the HhH-GPD domain (V118-249W aa) with a function in base-excision repair (PMID: 10706276). Experimental studies showed this missense change abolishes the glycosylase activity of the MUTYH protein (PMID: 20418187, 19953527) (PS3 Pathogenic Strong). It is in a mutation hotspot of 7 pathogenic, including missense pathogenic variants (PM1 Pathogenic Moderate). The allele frequency in GnomAD exomes is 0.00000795 which is less the threshold 0.0001 for recessive gene MUTYH, and the variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). Meantime, majority of missense variants detected in MUTYH are pathogenic and known cause of disease (PP2 Pathogenic Supporting). In our study this variant was found in a 54-year-old female patient with unilateral breast cancer and a family history of cancer. Based on the evidence above we classified this variant as a Variant of Unknown Significance.

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