ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.849+3A>C (rs587780751)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123158 SCV000166462 pathogenic MYH-associated polyposis 2020-10-30 criteria provided, single submitter clinical testing This sequence change falls in intron 10 of the MUTYH gene. It does not directly change the encoded amino acid sequence of the MUTYH protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs587780751, 0.01%). This variant has been observed as homozygous or in trans with pathogenic variants in multiple individuals affected with adenomatous polyposis and it is considered a founder mutation for MUTYH-associated polyposis in North-Eastern Italy (PMID: 12853198, 16616356, 19732775, 22773231, 22865608). This variant is also known as c.891+3A>C in the literature. Clinvar contains an entry for this variant (Variation ID: 135992). This variant falls in intron 10 of the MUTYH mRNA and is reported to cause skipping of exon 10 (PMID: 16616356, 22865608). The absence of exon 10 in the MUTYH mRNA results in a translational frameshift and premature stop codon (p.Gly264TrpfsX7), which ultimately leads to nonsense mediated decay and severely impaired expression of the MUTYH mRNA and protein (PMID: 16616356, 22865608, 23108399). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000129539 SCV000184317 pathogenic Hereditary cancer-predisposing syndrome 2018-10-01 criteria provided, single submitter clinical testing ​The c.933+3A>C intronic pathogenic mutation results from an A to C substitution three nucleotides after coding exon 10 in the MUTYH gene. This alteration has been well described in the literature. In one study, the c.933+3A>C alteration was identified in conjunction with another MUTYH mutation in eighteen individuals with MUTYH-associated polyposis (Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85). This alteration has also been described as a founder mutation in the Northeastern Italian and German populations (Pin E et al. Int. J. Cancer. 2013 Mar;132:1060-9). RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Of note,<span style="background-color:initial"> this alteration is also designated as c.891+3A>C in published literature. Based on the available evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000212711 SCV000211413 pathogenic not provided 2018-11-21 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.933+3A>C or IVS10+3A>C and consists of an A>C nucleotide substitution at the +3 position of intron 10 of the MUTYH gene. This variant, also published as 891+3A>C or Gly250TrpfsX7, has been reported in multiple polyposis and colorectal cancer patients, is considered a founder variant in Italian populations, and has been demonstrated to cause skipping of exon 10 (Sampson 2003, Kanter-Smoler 2006, Olschwang 2007, Vogt 2009, Pin 2012, Ruggieri 2013, Yurgelun 2015). MUTYH c.933+3A>C was observed at an allele frequency of 0.01% (17/126656) in individuals of European ancestry in large population cohorts (Lek 2016). Based on the current evidence, we consider this variant to be pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000212711 SCV000331108 pathogenic not provided 2015-07-09 criteria provided, single submitter clinical testing
Counsyl RCV000123158 SCV000487342 pathogenic MYH-associated polyposis 2016-03-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129539 SCV000537683 pathogenic Hereditary cancer-predisposing syndrome 2020-10-12 criteria provided, single submitter clinical testing This variant causes an A to C nucleotide substitution at the +3 position of intron 10 of the MUTYH gene. This variant is also known as IVS10+3A>C or as c.891+3A>C based on alternative transcript (NM_001048171). Functional RNA studies have shown that this variant causes skipping of exon 10, resulting in a frameshift and premature stop codon (p.Gly264Trpfs*7) (PMID: 16616356, 22865608). This variant is expected to result in an absent or non-functional protein product. This variant has been reported as homozygous or in trans with pathogenic variants in multiple individuals affected with adenomatous polyposis (PMID: 12853198, 16616356, 19732775, 22773231, 22865608) and it is known to be a founder mutation in Western Europe (PMID: 22865608). This variant has been identified in 21/282792 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000123158 SCV000697716 pathogenic MYH-associated polyposis 2016-02-08 criteria provided, single submitter clinical testing Variant summary: MUTYH c.933+3A>C variant affects a non-conserved intronic nucleotide. Mutation Taster predicts a damaging outcome for this variant, and 5/5 Alamut algorithms predict the variant to alter normal splicing, which is supported by patient cDNA showing that this variant results in a fusion of exon 9 to exon 11. This variant is found in 8/124162 control chromosomes at a frequency of 0.0000644, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0055902). However, the variant has been cited in numerous CRC patients in the literature. In addition, several diagnostic clinical laboratories and databases classified this variant as pathogenic. Taken together, this is a disease variant and was classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000123158 SCV000711785 pathogenic MYH-associated polyposis 2016-03-28 criteria provided, single submitter clinical testing The c.933+3A>C variant in MUTYH has been previously reported in 24 individuals ( 23 were compound heterozygotes, 1 was a homozygote, and 1 was a heterozygote) wi th MUTYH-related attenuated familial adenomatous polyposis (FAP)and segregated w ith disease in 7 affected family members (Sampson 2003, Vogt 2009, Pin 2013). It has been identified in 7/66554 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs587780751). This freq uency is low enough to be consistent with the carrier frequency of MUTYH-related attenuated FAP in the general population. This variant is located in the 5' spl ice region. Computational tools do suggest an impact to splicing and functional studies provide evidence that this variant alters splicing (Pin 2013). In summar y, this variant meets criteria to be classified as pathogenic for FAP in an aut osomal recessive manner based on the reported number of probands, segregations, and functional studies.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626760 SCV000747463 uncertain significance Malignant tumor of colon 2017-01-01 criteria provided, single submitter clinical testing
Mendelics RCV000123158 SCV000837759 pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000123158 SCV000993568 pathogenic MYH-associated polyposis 2018-10-10 criteria provided, single submitter research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212711 SCV001134490 pathogenic not provided 2019-01-18 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to negatively affect a known splice site. Nucleotide conservation is uninformative. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212711 SCV001248080 pathogenic not provided 2020-07-01 criteria provided, single submitter clinical testing
Department of Pediatrics,Memorial Sloan Kettering Cancer Center RCV000123158 SCV001478130 pathogenic MYH-associated polyposis 2020-12-15 criteria provided, single submitter research
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000123158 SCV001499745 pathogenic MYH-associated polyposis 2020-04-02 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000212711 SCV001713011 pathogenic not provided 2020-06-05 criteria provided, single submitter clinical testing PVS1, PS3, PM3, PP3, PP5
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353438 SCV000592702 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MUTYH c.933+3A>C variant was identified in 27 of 1210 proband chromosomes (frequency: 0.022) from individuals or families with polyposis coli or colorectal cancer, and was not identified in 340 control chromosomes from healthy individuals (Kanter-Smoler 2006, Nielsen 2005, Pin 2013, Sampson 2003, Vogt 2009). Most of the probands described in these studies were heterozygous for the variant and had a second MUTYH variant (compound heterozygotes); while one proband from a study by Pin (2013) was homozygous for the variant. The variant was also identified in the “InSiGHT Colon Cancer Database”, HGMD, UMD (33X as a causal variant) and the ClinVar database (with “pathogenic” clinical significance, submitted by Ambry Genetics and Invitae). The c.933+3A>C variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. Four out of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. Analysis of mRNA in functional studies by Ruggieri (2013) and Pin (2013) have shown that this variant affects splicing, resulting skipping of exon 10 in mRNA transcripts. Protein analysis from these studies demonstrated reduced levels of MUTYH protein, although the amount of protein varied greatly, depending on the second MUTYH mutation in compound heterozygotes. Pin (2013) notes that traces of full-length transcripts and wild-type protein were found in cells homozygous for the variant, suggesting some transcripts may escape from aberrant splicing. The authors of this study found this in agreement with clinical findings in a homozygous proband, who presented with a relatively mild phenotype (attenuated polyposis). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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