ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.1105del (p.Ala371fs) (rs587778536)

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Total submissions: 19
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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 2018-06-28 criteria provided, single submitter clinical testing The c.1147delC pathogenic mutation, located in coding exon 12 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 1147, causing a translational frameshift with a predicted alternate stop codon (p.A385Pfs*23). This alteration has been reported in a homozygous and compound heterozygous state in multiple individuals with polyposis and has been described as a European founder mutation (Eliason K et al. J. Med. Genet. 2005 Jan;42:95-6; Nielsen M et al. Gastroent. 2009 Feb;136:471-6; Pin E et al. Int. J. Cancer. 2013 Mar;132:1060-9; Ricci MT et al. J. Hum. Genet. 2017 Feb;62:309-315; Seguí N et al. Gut. 2015 Feb;64:355-6; Sieber OM et al. N. Engl. J. Med. 2003 Feb 27;348:791-9, Torrezan GT et al. Orphanet J Rare Dis. 2013 Apr;8:54; Vogt S et al. Gastroent. 2009 Dec;137:1976-85.e1-10). Functional studies indicate c.1147delC leads to a protein devoid of glycosylase and DNA binding activity (Ali M et al. Gastroent. 2008 Aug;135:499-507), as well as a 50-100% decrease in MUTYH protein expression levels compared to wild-type levels in a compound heterozygous state (Pin E et al. Int. J. Cancer. 2013 Mar;132:1060-9; Ruggieri V et al. Oncogene. 2013 Sep;32:4500-8). Of note, this alteration is also designated as c.1103delC, c.1105delC, and c.1145delC in published 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.
Invitae RCV000196379 SCV000253862 pathogenic MYH-associated polyposis 2020-10-21 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 observed in individual(s) 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.
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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235584 SCV000601627 pathogenic not provided 2017-03-23 criteria provided, single submitter clinical testing
Counsyl RCV000196379 SCV000678198 pathogenic MYH-associated polyposis 2015-11-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000164291 SCV000685545 pathogenic Hereditary cancer-predisposing syndrome 2020-09-08 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 12 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is also known as c.1105delC, c.1103delC and c.1063delC in the literature. This variant is expected to result in an absent or non-functional protein product. Functional studies have found this variant to cause MUTYH protein instability and impaired DNA repair activities in carrier cells and abolished glycosylase and DNA binding activities in vitro (PMID: 15987719, 18534194. 23108399). This variant has been observed in multiple homozygous and biallelic carriers affected with polyposis and/or colorectal cancer (PMID: 12606733, 15635083, 16140997, 16557584, 17368238, 22266422, 22865608, 23561487, 27829682) and has been observed to segregate in 5 affected members of one Lynch syndrome family (PMID: 24691292). This variant has been identified in 18/281328 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as 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
Mendelics RCV000196379 SCV000837754 pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000196379 SCV000917797 pathogenic MYH-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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000235584 SCV001248079 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000196379 SCV001429542 uncertain significance MYH-associated polyposis 2017-05-09 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000235584 SCV001446530 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
ITMI RCV000121593 SCV000085789 not provided not specified 2013-09-19 no assertion provided reference population
Pathway Genomics RCV000144632 SCV000189959 pathogenic Carcinoma of colon 2014-07-24 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000144632 SCV000592709 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MUTYH p.Ala385Profsx23 deletion variant was identified in 51 of 1892 proband chromosomes (frequency: 0.027) from individuals or families with adenomatous polyposis or colon cancer (Aretz 2006, Nielsen 2009, Ruggieri 2013, Sieber 2003, Vogt 2009). Of these probands, two individuals were homozygous for the variant and the remaining individuals were compound heterozygotes, harbouring a second MUTYH variant. The variant was previously identified by our laboratory in three individuals with adenomatous polyposis. The variant was also identified in HGMD, the “InSiGHT Colon Cancer Database”, and the ClinVar database (submitted by Inova Translational Medicine Institute, clinical significance not provided). The p.Ala385Profsx23 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 385 and leads to a premature stop codon 23 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants in the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis. In addition, a cell line with the variant showed decreased levels of transcript and protein (Ruggieri 2013), and an in vitro study found that the variant protein had a lower molecular weight than wild-type protein and was devoid of glycosylase and DNA binding activities (Ali 2008). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
GeneReviews RCV000196379 SCV001167334 pathogenic MYH-associated polyposis 2019-10-08 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000235584 SCV001741659 pathogenic not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000235584 SCV001797625 pathogenic not provided no assertion criteria provided clinical testing

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