ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.857G>A (p.Gly286Glu) (rs730881833)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221854 SCV000278100 likely pathogenic Hereditary cancer-predisposing syndrome 2017-05-26 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
Color RCV000221854 SCV000685675 likely pathogenic Hereditary cancer-predisposing syndrome 2018-06-22 criteria provided, single submitter clinical testing
GeneDx RCV000160754 SCV000211408 pathogenic not provided 2018-10-22 criteria provided, single submitter clinical testing This pathogenic variant is denoted MUTYH c.857G>A at the cDNA level, p.Gly286Glu (G286E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGG>GAG). This variant, also reported as Gly272Glu using alternate nomenclature, has been observed in the homozygous or compound heterozygous state in at least four individuals with colorectal cancer and/or adenomatous polyposis (Yanaru-Fujisawa 2008, Zhang 2015, Khan 2017, Takao 2018). While one functional study found MUTYH Gly286Glu to retain base excision repair activity, other assays revealed this variant to impair DNA glycosylase activity (Yanaru-Fujisawa 2008, Komine 2015). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the APE1 binding domain (Parker 2001, Yang 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider MUTYH Gly286Glu to be pathogenic.
GeneReviews RCV000191933 SCV000246164 pathogenic MYH-associated polyposis 2015-09-24 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000780502 SCV000917807 likely pathogenic MUTYH-associated polyposis 2017-12-04 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.857G>A (p.Gly286Glu) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). A functional study, Yanaru-Fuhisawa_2008, supports these predictions with the observation that the variant impedes DNA glycosylase activity. This variant is absent in 246004 control chromosomes. Multiple publications cite the variant in affected individuals including one pt, who was homozygous for the variant (Yanaru-Fuhisawa_2008) and presented with rectal cancer and colorectal polyposis. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic/pathogenic." Taken together, this variant is classified as likely pathogenic.
Invitae RCV000191933 SCV000639360 likely pathogenic MYH-associated polyposis 2018-05-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 286 of the MUTYH protein (p.Gly286Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs730881833, ExAC 0.01%). This variant has been observed as homozygous or on the opposite chromosome (in trans) from pathogenic variants in MUTYH in individuals affected with polyposis, colon cancer, and rectal cancer (PMID: 18422726, 17703316, 25892863, Invitae). This variant is also known as c.815G>A p.G272E in the literature. ClinVar contains an entry for this variant (Variation ID: 182691). An experimental study has shown that this missense change impairs DNA glycosylase activity of MUTYH (PMID: 18422726). However, in another study, the variant could suppress spontaneous mutations comparable to wild-type protein in an E. Coli complementation assay (PMID: 25820570). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000191933 SCV000267404 likely pathogenic MYH-associated polyposis 2016-03-18 criteria provided, single submitter reference population

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