ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs758377868
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Total submissions: 8
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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.
Eurofins NTD LLC (GA) RCV000180208 SCV000232602 uncertain significance not provided 2015-01-12 criteria provided, single submitter clinical testing
Counsyl RCV000411665 SCV000487365 uncertain significance MUTYH-related attenuated familial adenomatous polyposis 2016-06-15 criteria provided, single submitter clinical testing
Invitae RCV000411665 SCV000545740 pathogenic MUTYH-related attenuated familial adenomatous polyposis 2021-08-31 criteria provided, single submitter clinical testing
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 MUTYH-related attenuated familial adenomatous polyposis 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000411665 SCV001774639 pathogenic MUTYH-related attenuated familial adenomatous polyposis 2021-07-26 criteria provided, single submitter clinical testing Variant summary: MUTYH c.577-5A>G alters a non-conserved nucleotide located close to a canonical 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: One predicts the variant abolishes a 3 acceptor site. Two predict the variant weakens a 3 acceptor site. Two predict the variant creates a 3 cryptic acceptor site. Additionally, at least two RNA studies report this variant causes aberrant splicing and shows the inclusion of the last four nucleotides of intron 7 [r.576_577ins(577-4_577-1)], which presumably would generate a truncated protein (p.Val165Serfs*61) (Landrith_2020, Rofes_2020). The variant allele was found at a frequency of 4e-06 in 252164 control chromosomes (gnomAD and publication data). c.577-5A>G has been reported in the literature in two individuals affected with severe polyposis and one homozygous individual with personal and family records of colorectal polyps (Landrith_2020, Rofes_2020). These data indicate that the variant is likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3), likely pathogenic (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000180208 SCV001779816 uncertain significance not provided 2020-03-03 criteria provided, single submitter clinical testing In silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing.; Reported to co-occur with a pathogenic founder MUTYH variant, phase unknown, in two individuals with severe polyposis (Landrith 2020); A published functional study suggests this variant may impact splicing (Landrith 2020); This variant is associated with the following publications: (PMID: 33011440, 32133419)

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