ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.1147del (p.Ala385fs) (rs587778536)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164291 SCV000214918 pathogenic Hereditary cancer-predisposing syndrome 2017-06-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other acmg-defined mutation (i.e. initiation codon or gross deletion),Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Deficient protein function by in vitro/ex vivo assay,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
Color RCV000164291 SCV000685545 pathogenic Hereditary cancer-predisposing syndrome 2016-06-23 criteria provided, single submitter clinical testing
Counsyl RCV000196379 SCV000678198 pathogenic MYH-associated polyposis 2015-11-06 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000196379 SCV000592709 pathogenic MYH-associated polyposis 2014-10-27 criteria provided, single submitter clinical testing
GeneDx RCV000235584 SCV000292629 pathogenic not provided 2018-08-15 criteria provided, single submitter clinical testing This deletion of one nucleotide in MUTYH is denoted c.1147delC at the cDNA level and p.Ala385ProfsX23 (A385PfsX23) at the protein level. The normal sequence, with the base that is deleted in braces, is GGCC[C]TTGG. The deletion causes a frameshift, which changes an Alanine to a Proline at codon 385, and creates a premature stop codon at position 23 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MUTYH c.1147delC, also published as MUTYH c.1103delC, c.1105delC, c.1138delC, and c.1145delC, has been reported in both the homozygous and compound heterozygous state in multiple individuals with MUTYH-associated polyposis (Sieber 2003, Aretz 2006, Vogt 2009, Nielsen 2009, Giraldez 2010, Morak 2010, Pin 2013, Ruggieri 2013, Segui 2015). Additionally, Ali et al. (2008) showed that MUTYH c.1147delC is dysfunctional with respect to both DNA binding and base excision repair activities while Ruggieri et al. (2013) demonstrated that this variant, in the compound heterozygous state with a second truncating MUTYH variant, was associated with a 50% decrease in MUTYH expression levels when compared to wild-type. We therefore consider MUTYH c.1147delC to be pathogenic.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000626290 SCV000746949 likely pathogenic Familial colorectal cancer 2017-12-18 criteria provided, single submitter clinical testing
ITMI RCV000121593 SCV000085789 not provided not specified 2013-09-19 no assertion provided reference population
Illumina Clinical Services Laboratory,Illumina RCV000196379 SCV000915416 pathogenic MYH-associated polyposis 2018-10-04 criteria provided, single submitter clinical testing The MUTYH c.1105delC (p.Ala371ProfsTer23) variant causes a frameshift, and is predicted to result in premature termination of the protein. Truncating variants in the MUTYH gene are known to be disease-causing. Across five studies as a representation of the available literature, the p.Ala371ProfsTer23 variant was identified in a total of 17 individuals with polyposis including sixteen in a compound heterozygous state and one in a homozygous state (Sieber et al. 2003; Nielsen et al. 2005; Aretz et al. 2006; Middeldorp et al. 2008; Laarabi et al. 2012). The variant was absent from 223 control subjects and is reported at a frequency of 0.001212 in the European American population of the Exome Sequencing Project. Functional studies demonstrate that the p.Ala371ProfsTer23 variant results in a truncated protein expressed at <1% of wild type levels which is completely devoid of glycosylase and DNA binding activities. These results are supported by position of the variant with respect to the domain structure of the protein where the variant is predicted to cause the loss of the catalytic domain of the enzyme (Ali et al. 2008; Ruggierie et al. 2013). Based on the collective evidence, the p.Ala371ProfsTer23 variant is classified as pathogenic for MYH-associated polyposis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000780495 SCV000917797 pathogenic MUTYH-associated polyposis 2017-09-12 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.1147delC (p.Ala385ProfsX23) variant results in a premature termination codon, predicted to cause a truncated or absent MUTYH 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 (e.g., c.1227_1228dupGG [p.Glu410fsX43] and c.1435G>T [p.Glu479X]). MutationTaster predicts a damaging outcome for this variant. This variant was found in 9/119682 control chromosomes at a frequency of 0.0000752, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). The variant has been identified in numerous MAP patients, including homozygous family members (Vogt_2009). In addition, functional studies show that the variant is completely defective in glycosylase and DNA binding activities (Ali_2008). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000196379 SCV000253862 pathogenic MYH-associated polyposis 2018-12-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala385Profs*23) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587778536, ExAC 0.01%). This variant has been reported in individuals affected with multiple colorectal adenomas (PMID: 12606733, 23108399, 19732775, 23561487). This variant is also known as c.1103delC and c.1145delC in the literature. ClinVar contains an entry for this variant (Variation ID: 134860). Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000196379 SCV000837754 pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Pathway Genomics RCV000144632 SCV000189959 pathogenic Carcinoma of colon 2014-07-24 no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235584 SCV000601627 pathogenic not provided 2017-03-23 criteria provided, single submitter clinical testing

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