ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.504G>A (p.Glu168=) (rs876658641)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222177 SCV000274164 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-07 criteria provided, single submitter clinical testing The c.504G>A variant (also known as p.E168E), located in coding exon 6 of the MUTYH gene, results from a G to A substitution at nucleotide position 504. This nucleotide substitution does not change the amino acid at codon 168; however, this change occurs at the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. This alteration is predicted by the BDGP splicing model to abolish the native splice donor site and is predicted to weaken (but not abolish) the efficacy of this native site by the ESEfinder in silico tool; however, direct evidence is unavailable. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of c.504G>A remains unclear.
Invitae RCV000471395 SCV000545710 uncertain significance MYH-associated polyposis 2019-09-26 criteria provided, single submitter clinical testing This sequence change affects codon 168 of the MUTYH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MUTYH protein. This variant also falls at the last nucleotide of exon 6 of the MUTYH coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MUTYH-related conditions. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000222177 SCV000685636 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264555 SCV001442764 uncertain significance not specified 2020-10-09 criteria provided, single submitter clinical testing Variant summary: MUTYH c.504G>A (p.Glu168Glu) alters a conserved nucleotide located at the last position of exon 6 adjacent to the canonical donor splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250620 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.504G>A in individuals affected with MUTYH-Associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Three 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.

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