ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.934-2A>G (rs77542170)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000034683 SCV000166463 likely pathogenic MYH-associated polyposis 2019-01-02 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 10. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs77542170, ExAC 1.4%) with an elevated carrier frequency in the Asian population (PMID: 24728327, 15180946, 17703316, 18271935). This variant has been reported as heterozygous in several individuals with colorectal adenomas, colorectal carcinomas (PMID: 15890374, 17703316), and/or breast cancer (PMID: 15890374, 17703316, 26824983). In all of these individuals, this variant was the only pathogenic variant identified for this typically autosomal recessive gene. Importantly, the evidence from these reports is insufficient to determine whether this heterozygous variant alone is causative for disease. In the literature, this variant is also known as c.892-2A>G and IVS10-2A>G. ClinVar contains an entry for this variant (Variation ID: 41766). RNA analysis of individuals with this variant indicates that it leads to inclusion of intron 10 and a premature termination codon (PTC) in the MUTYH mRNA (PMID: 15180946). While a PTC is expected to result in nonsense mediated decay (NMD) and loss of the mutant mRNA, protein analysis of this variant indicates that a truncated MUTYH protein is expressed, but preferentially localized to the cytoplasm in a human cell line. Since the wild-type MUTYH protein is predominantly localized to the nucleus, this data suggests that this splice site variant disrupts protein function. In summary, donor and acceptor splice site variants are typically truncating (PMID: 16199547), and the truncated protein generated by this splice site variant has been shown to behave aberrantly in cell culture (PMID: 15180946). This evidence strongly suggests that the variant is pathogenic, but the available data is currently insufficient to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000129053 SCV000183748 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence,Functionally-validated splicing mutation ,Deficient protein function by in vitro/ex vivo assay,Intact protein function observed by in vitro/ex vivo assays,Sub-population frequency in support of benign classification (not ava blue, manual h-w)
GeneDx RCV000212712 SCV000211414 likely pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.934-2A>G or IVS10-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 10 of the MUTYH gene. Using an alternate transcript, this variant has been reported as MUTYH c.892-2A>G. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Tao et al. (2004) and Taki et al. (2015) have independently shown that MUTYH c.934-2A>G results in an aberrant mRNA transcript which retains intron 10, has a premature stop codon in exon 11, and encodes a truncated protein. In addition, in vitro expression studies demonstrate that, if translated, the variant protein, in contrast to wild-type expressed protein, is not localized in the nucleus, suggesting insufficient ability of the variant to repair nuclear DNA (Tao 2004). However, this variant has not, to our knowledge, been published in the literature in the homozygous or compound heterozygous state in an individual with a phenotype consistent with MUTYH-associated polyposis (MAP). MUTYH c.934-2A>G was observed at an allele frequency of 1.5% (293/18,870) in individuals of East Asian ancestry in large population cohorts (Lek 2016) and has been described in the literature as a common variant in Japanese individuals (Tao 2004, Miyaki 2005). Based on currently available evidence, we consider MUTYH c.934-2A>G to be a likely pathogenic variant.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000122431 SCV000221200 uncertain significance not specified 2017-09-01 criteria provided, single submitter clinical testing The c.934-2A>G variant has been widely studied in the East Asian population and reported in at least 7 individuals with colorectal cancer; however, to our knowl edge, none of these individuals had a second pathogenic germline MUTYH variant i dentified (Miyaki 2005, Kim 2007, Taki 2016). This variant has been identified i n 1.6% (294/18944) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs77542170). The c.934-2A>G var iant occurs in the invariant region (+/- 1,2) of the splice consensus sequence a nd was demonstrated to cause aberrant splicing in in vitro studies (Tao 2004, Ta ki 2016), but whether this alteration causes a biological loss of function of th e MUTYH protein in humans is uncertain. In summary, while the predicted function al impact of this variant and in vitro studies favor a pathogenic role, based on the absence of reported affected individuals carrying this variant and a second pathogenic MUTYH variant in the literature despite its high frequency in the ge neral population, its clinical significance is uncertain. Additional studies are needed to clarify the significance of this variant.
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000034683 SCV000267403 pathogenic MYH-associated polyposis 2016-03-18 criteria provided, single submitter reference population
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212712 SCV000601664 likely pathogenic not provided 2017-04-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212712 SCV000697717 uncertain significance not provided 2016-11-10 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.934-2A>G variant involves the alteration of a conserved intronic nucleotide. Mutation taster predicts a damaging outcome for this substitution along with 5/5 splice site predicting tools predicting the variant to result in loss of the splice acceptor site in intron 10. A functional study showed that the variant may lead to an aberrant mRNA transcript that retains the full intron 10 sequence and result in a truncated MUTYH protein. 3/5 splice site predicting tools predict that an alternative 3' splicing acceptor site is located 9 bps down stream to the canonical 3' splicing acceptor site in exon 11, which may generate an alternative protein with removal of 3 amino acids. This alternative protein may retain the normal function. No functional study has tested if this alternative transcript is expressed. The variant was found in several, mostly East Asian patients with colorectal polyps and/or colorectal, gastric and breast cancers. To our knowledge, only one homozygous patient has been described to date that had gastric cancer while the rest of the reported patients harbored the variant in heterozygosity. In the general population, this variant was found in 147/123022 control chromosomes (1 homozygote) at a frequency of 0.0011949, it is most prevalent in the East Asian population where the allele frequency (0.014) exceeds three times the maximal expected allele frequency of a disease causing MUTYH allele (0.0045) indicating the variant to either have a low penetrance or to be in the benign spectrum. However, immunofluorescence analysis showed that the wild-type MUTYH protein, but not the truncated protein, is localized in the nucleus suggesting insufficient ability of the variant-type protein to repair nuclear DNA indicating causality. Multiple clinical diagnostic laboratories/reputable databases classified this variant as VUS or likely pathogenic. Due to conflicting evidence, the pathogenicity or neutrality of the variant cannot be established with certainty at this time, therefore it was classified as a VUS.
Mendelics RCV000034683 SCV000837758 likely pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000129053 SCV000910559 likely pathogenic Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034683 SCV000043373 probably pathogenic MYH-associated polyposis 2012-07-13 no assertion criteria provided research Converted during submission to Likely pathogenic.
ITMI RCV000122431 SCV000083982 not provided not specified 2013-09-19 no assertion provided reference population

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