ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.504G>C (p.Glu168Asp) (rs587781645)

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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 RCV000129775 SCV000184584 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-15 criteria provided, single submitter clinical testing The p.E196D variant (also known as c.588G>C), located in coding exon 8 of the MUTYH gene, results from a G to C substitution at nucleotide position 588. The glutamic acid at codon 196 is replaced by aspartic acid, an amino acid with highly similar properties. 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.
GeneDx RCV000484778 SCV000565254 uncertain significance not provided 2015-08-05 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.588G>C at the cDNA level, p.Glu196Asp (E196D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Glu196Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. MUTYH Glu196Asp occurs at a position that is conserved in mammals and is not located in a known functional domain (Ruggieri 2013, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MUTYH Glu196Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000539493 SCV000639344 uncertain significance MYH-associated polyposis 2020-09-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 196 of the MUTYH protein (p.Glu196Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs587781645, ExAC 0.003%). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 141306). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Color Health, Inc RCV000129775 SCV000690589 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-09 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with aspartic acid at codon 196 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/251470 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.
GeneKor MSA RCV000129775 SCV000822076 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000539493 SCV000837770 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001375560 SCV001572440 uncertain significance not specified 2021-04-01 criteria provided, single submitter clinical testing Variant summary: MUTYH c.588G>C (p.Glu196Asp) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251470 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.588G>C has been reported in the literature in individuals screened for hereditary cancer (e.g. Tsaousis_2019). These reports 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 other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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