ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000191933 SCV000267404 likely pathogenic MYH-associated polyposis 2016-03-18 criteria provided, single submitter reference population
Ambry Genetics RCV000221854 SCV000278100 pathogenic Hereditary cancer-predisposing syndrome 2020-07-09 criteria provided, single submitter clinical testing The p.G286E pathogenic mutation (also known as c.857G>A) is located in coding exon 10 of the MUTYH gene. This alteration results from a G to A substitution at nucleotide position 857. The glycine at codon 286 is replaced by glutamic acid, an amino acid with very few similar properties. A Chinese patient with colon cancer diagnosed at age 40 and his sister with colon polyps were found to have this variant in conjunction with another MUTYH alteration, p.Q267* (Zhang JX et al. World J. Gastroenterol. 2015 Apr; 21(14):4136-49). This alteration was reported in a Korean male diagnosed with rectal cancer at age 39 in addition to 36 polyps and it was seen in conjunction with MUTYH p.Q260* in a Japanese patient with 100-200 polyps (Kim DW et al. Int J Colorectal Dis. 2007 Oct;22(10):1173-8; Takao M et al. Int. J. Clin. Oncol. 2018 Jun;23:497-503). This alteration was also reported in conjunction with MUTYH p.S332S in a Chinese patient with pancreatic cancer diagnosed at age 45 and a history of four colorectal adenomatous polyps; her family history was significant for a brother diagnosed with colorectal cancer at age 54 and a total of 30 adenomatous polyps, a sister with multiple colon polyps, and father diagnosed with pancreatic cancer (Thibodeau ML et al. Cold Spring Harb Mol Case Stud. 2019 04;5:). In another study, this alteration was identified in the homozygous state in an individual from Japan diagnosed with adenomatous polyposis as well as five gastric carcinomas and a functional assay demonstrated impaired glycoylase activity (Yanaru-Fujisawa R et al. Clin Genet. 2008 Jun;73(6):545-53). In another functional study, this alteration had mutation suppression levels similar to wild type, but defective glycosylation levels (Komine K et al. Hum. Mutat. 2015 Jul;36(7):704-11). In addition, this variant was detected in the homozygous state in multiple individuals with polyposis by our laboratory (Ambry internal data). Of note, this alteration was previously designated as p.G272E in the literature. 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000191933 SCV000639360 pathogenic MYH-associated polyposis 2020-10-01 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, 29330641, 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). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000221854 SCV000685675 likely pathogenic Hereditary cancer-predisposing syndrome 2019-06-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000191933 SCV000917807 likely pathogenic MYH-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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160754 SCV001134488 pathogenic not provided 2019-01-25 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Predicted to have a damaging effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Results on protein functions were conflicting.
GeneReviews RCV000191933 SCV000246164 pathogenic MYH-associated polyposis 2019-10-08 no assertion criteria provided literature only

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