ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.690G>A (p.Gln230=) (rs199989617)

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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 RCV000567080 SCV000666478 pathogenic Hereditary cancer-predisposing syndrome 2020-10-14 criteria provided, single submitter clinical testing The c.690G>A pathogenic mutation (also known as p.Q230Q), located in coding exon 8 of the MUTYH gene, results from a G to A substitution at nucleotide position 690. This nucleotide substitution does not change the glutamine at codon 230. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This variant has been reported as compound heterozygous in individuals with colorectal polyposis; furthermore, this mutation has been shown to result in aberrant splicing with exon 8 skipping by RT-PCR analysis (Ambry internal data; Vogt S et al. Gastroenterology 2009 Dec; 137(6):1976-85.e1-10; Dallosso AR et al. Gut 2008 Sep; 57(9):1252-5). Of note, this mutation is also designated as c.681G>A in the published literature. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000702233 SCV000831079 likely pathogenic MYH-associated polyposis 2020-09-24 criteria provided, single submitter clinical testing This sequence change affects codon 230 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 8 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 been reported in individuals affected with MUTYH-associated polyposis and has been observed on the opposite chromosome (in trans) from a pathogenic variant in at least two of these individuals (PMID: 19732775, 25559809). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 481804). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). An experimental study has shown that this silent change can results in skipping of exon 8 or exons 8-9 of the MUTYH mRNA. (PMID: 18515411). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759166 SCV000888323 likely pathogenic not provided 2018-03-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000567080 SCV000913515 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-14 criteria provided, single submitter clinical testing

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