ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.563_576+1del (rs766553845)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000640379 SCV000761970 uncertain significance MYH-associated polyposis 2017-10-04 criteria provided, single submitter clinical testing This sequence change deletes 15 nucleotides from exon 7 and intron 7 of the MUTYH mRNA (c.563_576+1del). This leads to the deletion of 5 amino acid residues in the MUTYH protein (p.Glu188_Lys192del) but otherwise preserves the adjacent donor splice site and the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with MUTYH-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780504 SCV000917810 uncertain significance not specified 2018-08-01 criteria provided, single submitter clinical testing Variant summary: MUTYH c.563_576+1del involves the deletion of 15 nucleotides from exon 7 and intron 7, leading to an in-frame deletion of 5 amino acids (p.Glu188_Lys192del). 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 246264 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.563_576+1del in individuals affected with MUTYH-associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV001024342 SCV001186341 likely pathogenic Hereditary cancer-predisposing syndrome 2019-07-01 criteria provided, single submitter clinical testing The c.563_576+1del15 intronic variant, located between coding exon 7 and intron 7 of the MUTYH gene, results from a deletion of the last 14 nucleotides of coding exon 7 and the first nucleotide within intron 7 of the MUTYH gene. This alteration has been detected in conjunction with the MUTYH p.G369D mutation in a patient with early-onset colorectal cancer and polyposis (Ambry internal data). Using the BDGP and ESEfinder splice site prediction tools, the donor site is shifted upstream leading to an in-frame deletion; 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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