ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.1423G>A (p.Ala475Thr) (rs587782263)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130986 SCV000185906 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-31 criteria provided, single submitter clinical testing The p.A489T variant (also known as c.1465G>A), located in coding exon 14 of the MUTYH gene, results from a G to A substitution at nucleotide position 1465. The alanine at codon 489 is replaced by threonine, an amino acid with similar properties. This variant has been reported in conjunction with two pathogenic mutations in the MUTYH gene in a male with polyposis, jaw exostosis and sebaceous cysts at age 34 (Kairupan CF et al. Int. J. Cancer 2005 Aug;116:73-7), and in an individual with 20 polyps at age 51 and breast cancer diagnosed at age 48 (Jo WS et al. Clin. Gastroenterol. Hepatol. 2005 Oct;3:1022-8). The MUTYH c.933+3A>C and p.A489T variants have co-occurred multiple times with other known MUTYH pathogenic mutations in unrelated individuals who are affected with polyposis, however the phase has not been determined (Kairupan CF et al. Int. J. Cancer. 2005 Aug;116(1):73-7; Ambry internal data). The p.A489T variant has also been reported as a monoallelic variant in an individual with an attenuated familial adenomatous polyposis phenotype (Morak M et al. Clin. Genet. 2010 Oct;78:353-63). An assay measuring base-excisional repair function found this alteration to result in partially defective protein function (Komine K et al. Hum. Mutat. 2015 Jul;36(7):704-11). Of note, this alteration is also designated as p.A475T (c.1423G>A) in published literature. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000203814 SCV000261194 uncertain significance MYH-associated polyposis 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 489 of the MUTYH protein (p.Ala489Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs587782263, ExAC 0.01%). This variant has been observed in individuals with colorectal polyposis and segregates with disease in a family (PMID: 16234049, Invitae, external communication). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as G1423A (A475T) in the literature. ClinVar contains an entry for this variant (Variation ID: 142138). This variant has been reported to partially affect MUTYH protein function in a bacterial model system (PMID: 25820570). The clinical significance of this result is uncertain at this time. 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.
GeneDx RCV000486816 SCV000568578 uncertain significance not provided 2018-08-21 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1465G>A at the cDNA level, p.Ala489Thr (A489T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC). This variant, also reported as MUTYH c.1423G>A or Ala475Thr using an alternate reference sequence, has been observed with a second pathogenic MUTYH variant in at least two individuals with multiple polyps (Kairupan 2005, Jo 2005). This variant has also been found as a single monoallelic variant in an individual with an attenuated FAP phenotype (Morak 2010). In one yeast-based complementation assay this variant demonstrated partially defective base excision repair activity (Komine 2015). MUTYH Ala489Thr was observed at an allele frequency of 0.012% (3/24,020) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located within the NUDIX domain (Ruggieri 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MUTYH Ala489Thr is pathogenic or benign. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.
Color Health, Inc RCV000130986 SCV000685584 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-14 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 489 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown the mutant protein to be partially defective for base excision repair activity (PMID: 25820570). This variant has been reported in individuals affected with polyposis (PMID: 15761860, 16234049, 20618354, 25820570). However, it often co-occurs with another pathogenic variant MUTYH c.933+3A>C, suggesting it may be a linked polymorphism (Color internal data). This variant has been identified in 11/282784 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Counsyl RCV000203814 SCV000797927 uncertain significance MYH-associated polyposis 2018-02-20 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000486816 SCV000806345 uncertain significance not provided 2018-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781620 SCV000919797 uncertain significance not specified 2019-07-18 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1465G>A (p.Ala489Thr) results in a non-conservative amino acid change located in the MutY, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251694 control chromosomes, predominantly at a frequency of 0.00012 within the African or African-American subpopulation in the gnomAD database. c.1465G>A has been reported in the literature in individuals affected with MUTYH-associated Polyposis (Kairupan_2005, Jo_2005, Morak_2010). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 32% of normal base excision repair (BER) glycosylase activity (Komine_2015). Six ClinVar submissions (evaluation after 2014) cites the variant five times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000486816 SCV001713010 uncertain significance not provided 2020-06-05 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.