ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.493-5A>G (rs758377868)

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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 RCV000162459 SCV000212816 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-24 criteria provided, single submitter clinical testing The c.577-5A>G intronic variant results from an A to G substitution 5 nucleotides upstream from coding exon 8 in the MUTYH gene. This variant has been identified in conjunction with pathogenic MUTYH mutations in probands with adenomatous polyposis (Ambry internal data). This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice acceptor site. However, the Human Splicing Finder (HSF) software predicts the creation of a new alternate splice acceptor site, and the MaxEnt splice site prediction tool predicts a weakening of the native splice acceptor site efficiency (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000180208 SCV000232602 uncertain significance not provided 2015-01-12 criteria provided, single submitter clinical testing
Counsyl RCV000411665 SCV000487365 uncertain significance MYH-associated polyposis 2016-06-15 criteria provided, single submitter clinical testing
Invitae RCV000411665 SCV000545740 pathogenic MYH-associated polyposis 2020-10-27 criteria provided, single submitter clinical testing This sequence change falls in intron 7 of the MUTYH gene. It does not directly change the encoded amino acid sequence of the MUTYH protein. This variant is present in population databases (rs758377868, ExAC 0.006%). This variant has been reported in individuals in the Universal Mutation Database (PMID: 10612827) and the Leiden Open-source Variation Database (PMID: 21520333). This variant has been observed in individual(s) with clinical features of MUTYH-associated polyposis (Invitae, external communication). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 183746). 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. For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000162459 SCV000685648 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-19 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the -5 position of intron 7 of the MUTYH gene. A functional RNA study has shown that this variant causes aberrant splicing and results in a partial intron 7 retention (r.576_577ins577-4_577-1), which is predicted to cause a frameshift and premature protein truncation (PMID: 32133419). It has been shown that the mutant transcript constitutes about 16% relative transcript level in cells from a heterozygous carrier (PMID: 32133419). This variant has been observed together with a known pathogenic mutation, p.Gly396Asp, in the same gene in two individuals affected with severe polyposis (PMID: 32133419). This variant has been identified in 1/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Mendelics RCV000411665 SCV000837772 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing

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