ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.534G>A (p.Lys178=) (rs876660092)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217248 SCV000277223 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing The c.576G>A variant (also known as p.K192K), located in coding exon 7 of the MUTYH gene, results from a G to A substitution at nucleotide position 576. This nucleotide substitution does not change the at codon 192. However, this change occurs in the last base pair of coding exon 7, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV000269969 SCV000357901 uncertain significance MYH-associated polyposis 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000269969 SCV000639343 uncertain significance MYH-associated polyposis 2020-08-10 criteria provided, single submitter clinical testing This sequence change affects codon 192 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 7 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 disease. ClinVar contains an entry for this variant (Variation ID: 232945). 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.
Mendelics RCV000269969 SCV001135264 likely pathogenic MYH-associated polyposis 2019-05-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000217248 SCV001357640 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-21 criteria provided, single submitter clinical testing This synonymous variant alters the last conserved c.G nucleotide of exon 7 and is predicted to affect splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627) but has not been reported in individuals affected with polyposis or colorectal cancer in the literature. This variant has been identified in 2/282866 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.
GeneDx RCV001552803 SCV001773565 uncertain significance not provided 2020-02-18 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge

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