ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.14G>A (p.Arg5Gln) (rs587780081)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212697 SCV000149661 uncertain significance not provided 2018-06-27 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.56G>A at the cDNA level, p.Arg19Gln (R19Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has been observed in individuals with breast cancer, clinical manifestations of MUTYH-associated polyposis, or a Lynch syndrome-associated tumor and/or colon polyps (Tricarico 2011, Out 2012, Yurgelun 2015). Additionally this variant, reported as p.Arg5Gln using alternate nomenclature, was observed in a normal tissue sample from an individual with low grade glioma (Lu 2015). MUTYH Arg19Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the RPA binding domain (Ruggieri 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MUTYH Arg19Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two MUTYH pathogenic variants on opposite chromosomes.
Ambry Genetics RCV000115752 SCV000186396 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-08 criteria provided, single submitter clinical testing The p.R19Q variant (also known as c.56G>A), located in coding exon 2 of the MUTYH gene, results from a G to A substitution at nucleotide position 56. The arginine at codon 19 is replaced by glutamine, an amino acid with highly similar properties. In one study, this alteration was reported in a patient with breast cancer, diagnosed at less than 55 years of age, and this alteration was classified by the authors as a variant of unknown significance (Out AA et al. Breast Cancer Res Treat (2012) 134:219–227). This alteration was also observed in 1/182 individuals undergoing a 25-gene panel test for a clinical suspicion of Lynch syndrome (Yurgelun MB et al. Gastroenterology. 2015 May 13) and in 1/62 individuals with colorectal cancer and/or colon polyps who were tested for MUTYH mutations (Tricarico R et al. BMC Cancer, 2011 Jul;11:305). 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.
Invitae RCV000230254 SCV000285958 uncertain significance MYH-associated polyposis 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 19 of the MUTYH protein (p.Arg19Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587780081, ExAC 0.006%). This variant has been reported in individuals referred for Lynch syndrome testing or MUTYH-associated polyposis testing (PMID: 21777424, 25980754), and in an individual affected with breast cancer (PMID: 22297469). ClinVar contains an entry for this variant (Variation ID: 127834). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Counsyl RCV000230254 SCV000790004 uncertain significance MYH-associated polyposis 2017-03-14 criteria provided, single submitter clinical testing
Mendelics RCV000230254 SCV000837785 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115752 SCV000911086 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-08 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 19 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754, 21777424) and in an individual affected with breast cancer (PMID: 22297469). This variant has been identified in 7/251490 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194162 SCV001363472 uncertain significance not specified 2019-12-31 criteria provided, single submitter clinical testing Variant summary: MUTYH c.56G>A (p.Arg19Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251490 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.56G>A has been reported in the literature in at-least one individual undergoing clinical genetic testing for Lynch syndrome (Yurgelun_2015) and at-least one individual with breast cancer (Out_2012). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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.