ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.956-8G>A (rs757672024)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc RCV000581996 SCV000690622 likely benign Hereditary cancer-predisposing syndrome 2017-09-04 criteria provided, single submitter clinical testing
Counsyl RCV000667541 SCV000792010 likely benign MYH-associated polyposis 2017-06-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780498 SCV000917802 uncertain significance not specified 2018-03-16 criteria provided, single submitter clinical testing Variant summary: MUTYH c.998-8G>A 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. However, 5/5 computational tools predict no significant impact on normal splicing. Although, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.3e-05 in 219434 control chromosomes, predominantly at a frequency of 0.00014 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (2.3e-05 vs 0.0046), allowing no conclusion about variant significance. In addition, this observation in the control database needs to be cautiously considered due to the location being indicated as a low coverage site. To our knowledge, no occurrence of c.998-8G>A in individuals affected with MUTYH-associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. However, LOVD-InSight does report the variant to co-occur with a nonsense APC variant (exact variant not provided). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely benign." Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000667541 SCV000961932 uncertain significance MYH-associated polyposis 2020-10-27 criteria provided, single submitter clinical testing This sequence change falls in intron 11 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 (rs757672024, ExAC 0.002%). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 492067). 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. 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.

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