ClinVar Miner

Submissions for variant NM_001293192.1(MUTYH):c.-164del (rs587781704)

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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 RCV000129874 SCV000184691 pathogenic Hereditary cancer-predisposing syndrome 2019-02-14 criteria provided, single submitter clinical testing The c.91delG pathogenic mutation, located in coding exon 2 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 91, causing a translational frameshift with a predicted alternate stop codon (p.A31Pfs*27). This mutation has been detected as homozygous or as compound heterozygous in patients affected with polyposis (>10 polyps) (Inra JA et al. Genet. Med. 2015 Oct;17(10):815-21). In addition to the clinical data presented in the literature, 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.
GeneDx RCV000479390 SCV000565908 pathogenic not provided 2015-03-09 criteria provided, single submitter clinical testing This deletion of one nucleotide in MUTYH is denoted c.91delG at the cDNA level and p.Ala31ProfsX27 (A31PfsX27) at the protein level. The normal sequence, with the base that is deleted in brackets, is GGCA[G]CCAG. The deletion causes a frameshift, which changes an Alanine to a Proline at codon 31, and creates a premature stop codon at position 27 of the new reading frame. This variant has been reported in both the compound heterozygous and homozygous states in Caucasian individuals with multiple polyps (Inra 2015). MUTYH c.91delG 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 expected for an autosomal recessive disorder such as 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).
Invitae RCV000640397 SCV000761988 pathogenic MYH-associated polyposis 2019-10-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala31Profs*27) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. 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. ClinVar contains an entry for this variant (Variation ID: 141379). Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000479390 SCV000889535 pathogenic not provided 2018-02-19 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129874 SCV001339706 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000640397 SCV001361126 pathogenic MYH-associated polyposis 2019-05-14 criteria provided, single submitter clinical testing Variant summary: MUTYH c.91delG (p.Ala31ProfsX27) 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 (c.289C>T, p.Arg97X; c.1147delC, p.Ala385fsX23). The variant allele was found at a frequency of 2e-05 in 251478 control chromosomes (gnomAD). The variant, c.91delG, has been reported in the literature in multiple individuals affected with MUTYH-associated Polyposis (Inra_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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 pathogenic.

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