ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.325C>T (p.Arg109Trp) (rs765123255)

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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 RCV000162761 SCV000213238 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function by in vitro/ex vivo assay,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
Color RCV000162761 SCV000690558 likely pathogenic Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing
Counsyl RCV000230772 SCV000678193 likely pathogenic MYH-associated polyposis 2015-09-18 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000230772 SCV000592680 pathogenic MYH-associated polyposis 2015-03-02 criteria provided, single submitter clinical testing
GeneDx RCV000442590 SCV000517270 pathogenic not provided 2018-04-26 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.325C>T at the cDNA level, p.Arg109Trp (R109W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant, also published as c.283C>T, Arg95Trp and R81W using alternate transcripts, has been co-observed with the common pathogenic variant MUTYH Gly396Asp in a patient with colorectal cancer and 50 to 100 colorectal polyps (Vogt 2009) and in a patient with a Lynch syndrome-associated cancer and/or colon polyps (Yurgelun 2015). In addition, this variant has been observed to occur in trans with a pathogenic MUTYH variant in multiple individuals with clinical features suggestive of MUTYH-associated polyposis at this laboratory. MUTYH Arg109Trp was associated with decreased DNA glycosylase activity and decreased ability to suppress 8-hydroxyguanine-induced mutations compared to wild type in functional studies using human cell lines (Shinmura 2014). MUTYH Arg109Trp was observed at an allele frequency of 0.006% (2/30782) in individuals of South Asian ancestry 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 the currently available information, we consider MUTYH Arg109Trp to be a pathogenic variant. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.
Integrated Genetics/Laboratory Corporation of America RCV000588768 SCV000697691 likely pathogenic MUTYH-associated polyposis 2015-10-16 criteria provided, single submitter clinical testing
Invitae RCV000230772 SCV000285944 pathogenic MYH-associated polyposis 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 109 of the MUTYH protein (p.Arg109Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs765123255, ExAC 0.01%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with MUTYH-associated polyposis and colorectal cancer (CRC) (PMID: 19732775, 21520333). It also co-occurred with a pathogenic variant in an individual affected with suspected Lynch syndrome (PMID: 25980754), and was reported as heterozygous in an individual affected with early-onset CRC (PMID: 24799981). ClinVar contains an entry for this variant (Variation ID: 183896). Experimental studies have shown that this missense change disrupts the DNA glycosylase activity of the MUTYH protein in vitro, and its ability to suppress mutations in vivo (PMID: 24799981). For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000230772 SCV000538049 likely pathogenic MYH-associated polyposis 2016-03-30 criteria provided, single submitter clinical testing The c.325C>T (p.Arg109Trp) missense variant in the MUTYH gene has been previously reported in multiple individuals affected with Familial Adenomatous Polyposis (Vogt et al., 2009; Shinmura et al., 2014; Nielsen M et al., 2009). In two unrelated individuals, this variant was observed in trans with a known pathogenic variant, Gly396Asp (Vogt et al., 2009; Yurgelun MB et al., 2015). Furthermore, an in vitro functional assay demonstrated that this variant resulted in reduced DNA glycosylase activity and impaired mutation-suppression activity (Shinmura et al., 2014). This variant is reported at low frequency in the population databases (Exome Sequencing Project = NA; 1000 Genomes = NA; and ExAC = 0.006%). Multiple in silico algorithms predict this variant to have a deleterious effect (CADD = 15.47; PolyPhen = 1.0; SIFT = 0.0). Ambry Genetics has classified this variant as Likely pathogenic. Therefore, this collective evidence supports the classification of the c.325C>T (p.Arg109Trp) as a recessive Likely pathogenic variant for Familial Adenomatous Polyposis.
Mendelics RCV000230772 SCV000837782 pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing

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