ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.421-2A>C (rs786203161)

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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 RCV000166350 SCV000217138 likely pathogenic Hereditary cancer-predisposing syndrome 2019-12-12 criteria provided, single submitter clinical testing The c.505-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 7 in the MUTYH gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Invitae RCV000694454 SCV000822901 likely pathogenic MYH-associated polyposis 2020-03-12 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 of the MUTYH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. 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: 186709). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). 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.
Mendelics RCV000694454 SCV000837776 likely pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166350 SCV001736002 likely pathogenic Hereditary cancer-predisposing syndrome 2020-09-06 criteria provided, single submitter clinical testing This variant causes an A to C nucleotide substitution at the -2 position of intron 6 of the MUTYH gene. This variant may also be known as c.421-2A>C and c.463-2A>C in the literature based on different reference transcripts. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. 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. However, a different variant at the -1 position of this splice site with the same predicted splicing impact has been observed in an individual with a pathogenic MUTYH covariant and early-onset attenuated polyposis (PMID: 16557584, 19032956). This variant has been identified in 2/282836 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

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