ClinVar Miner

Submissions for variant NM_001293192.1(MUTYH):c.-97-64del (rs746449748)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479773 SCV000567734 pathogenic not provided 2015-08-18 criteria provided, single submitter clinical testing This deletion of one nucleotide in MUTYH is denoted c.200delG at the cDNA level and p.Gly67AlafsX24 (G67AfsX24) at the protein level. The normal sequence, with the base that is deleted in braces, is GCAG[G]CCTG. The deletion causes a frameshift, which changes a Glycine to an Alanine at codon 67, and creates a premature stop codon at position 24 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. we consider this variant to be pathogenic.Although this variant is considered pathogenic, a second mutation, as would be required for expression of the recessive condition MAP, was not detected in this individual. The possibility that this patient harbors a second disease-causing MUTYH mutation that is undetectable by this test cannot be excluded. While a single variant in the MUTYH gene has been reported in association with a slightly increased risk for colon cancer, endometrial cancer, and breast cancer, particularly among those with a family history of colorectal cancer (Jenkins 2006, Win 2011, Rennert 2012), there are conflicting data regarding these associations (Santonocito 2011, Out 2012). MUTYH-associated polyposis (MAP) is an autosomal recessive condition caused by two mutations (one affecting each allele) in the MUTYH gene which results in an increased risk for the development of colon cancer and colon polyps. If a MUTYH mutation carrier'spartner is also heterozygous for a MUTYH mutation, the risk to have a child with MAP is 25% with each pregnancy. One study from the UK estimated the overall carrier frequency for any MUTYH mutation to be about 2% (Aretz 2010).
Ambry Genetics RCV000493987 SCV000581683 pathogenic Hereditary cancer-predisposing syndrome 2018-06-29 criteria provided, single submitter clinical testing The c.200delG pathogenic mutation, located in coding exon 3 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 200, causing a translational frameshift with a predicted alternate stop codon (p.G67Afs*24). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000801139 SCV000917812 likely pathogenic MYH-associated polyposis 2018-11-06 criteria provided, single submitter clinical testing Variant summary: MUTYH c.200delG (p.Gly67AlafsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.289C>T (p.Arg97X), c.312C>A (p.Tyr104X), and c.1147delC (p.Ala385fsX23)). The variant allele was found at a frequency of 1.6e-05 in 245776 control chromosomes (gnomAD). To our knowledge, no occurrence of c.200delG in individuals affected with MUTYH-associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000801139 SCV000940904 pathogenic MYH-associated polyposis 2020-02-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly67Alafs*24) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs746449748, ExAC 0.003%). This variant has not been reported in the literature in individuals with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 419735). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). For these reasons, this variant has been classified as Pathogenic.

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