ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.305-1G>C (rs372267274)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221410 SCV000278764 pathogenic Hereditary cancer-predisposing syndrome 2018-04-24 criteria provided, single submitter clinical testing The c.389-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 5 of the MUTYH gene. This alteration has been identified as homozygous and in conjunction with other common pathogenic MUTYH mutations in multiple patients with 30-100 colorectal adenomas (Isidro G et al. Hum. Mutat. 2004 Oct;24:353-4; Torrezan GT et al. Orphanet J Rare Dis. 2013 Apr;8:54; Filipe B et al. Clin. Genet. 2009 Sep;76:242-55; Ambry internal data). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Of note, this alteration is also designated c.347-1G>C in published literature. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Invitae RCV000230931 SCV000285947 pathogenic MYH-associated polyposis 2019-12-12 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 of the MUTYH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous and in combination with another pathogenic MUTYH variant in individuals with colorectal polyposis (PMID: 15366000, 17949294, 23561487, Invitae). This variant is also known as c.347-1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 234229). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MUTYH are known to be pathogenic (PMID: 20663686, 18534194). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000230931 SCV000487337 pathogenic MYH-associated polyposis 2016-02-26 criteria provided, single submitter clinical testing
GeneDx RCV000478994 SCV000568584 pathogenic not provided 2018-08-29 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.389-1G>C or IVS4-1G>C and consists of a G>C nucleotide substitution at the -1 position of intron 4 of the MUTYH gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant, also reported as c.347-1G>C using alternate nomenclature, has been detected in trans with a second pathogenic MUTYH variant in several individuals with multiple colorectal adenomas (Isidro 2004, Filipe 2009, Torrezan 2013). Based on the current evidence, we consider this variant to be pathogenic.
Color Health, Inc RCV000221410 SCV000685623 pathogenic Hereditary cancer-predisposing syndrome 2020-09-14 criteria provided, single submitter clinical testing This variant causes a G to C nucleotide substitution at the -1 position of intron 4 splice acceptor site of the MUTYH gene. This variant is also known as c.347-1G>C based on the NM_001048171.1 transcript. Although functional studies have not been reported, this variant is expected to disrupt RNA splicing and result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with adenomatous polyposis in compound heterozygous state with pathogenic mutations (PMID: 15366000, 23561487; 19793053). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice acceptor site, c.389-1G>A and c.389-2A>G, are known to be disease-causing (Clinvar variation ID: 186819 and 215998). 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 RCV000230931 SCV000697693 pathogenic MYH-associated polyposis 2016-10-28 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.389-1G>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant abolishes the 3' splicing acceptor site in intron 4. This variant is absent in 121386 control chromosomes, however, has been reported in numerous MAP patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics RCV000230931 SCV000837780 pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478994 SCV000888315 pathogenic not provided 2017-12-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763342 SCV000894024 pathogenic MYH-associated polyposis; Pilomatrixoma; Neoplasm of stomach 2018-10-31 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV000230931 SCV001424796 pathogenic MYH-associated polyposis 2019-08-09 criteria provided, single submitter clinical testing The c.389-1G>C variant is predicted to lead to either nonsense-mediated mRNA decay or an abnormal protein product by destroying a canonical splice acceptor site. Loss-of-function variants in MUTYH are known to be pathogenic (Ali 2008, Nielsen 2011). The c.389-1G>C variant is not present in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). This variant has been reported in multiple individuals with MAP who are either homozygous or compound heterozygous for a second MUTYH pathogenic variant (Isidro 2004, Olschwang 2007, Torrezan 2013). Thus, this variant is interpreted as pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353991 SCV000592682 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The c.389-1G>C variant was identified in 3 of 152 proband chromosomes (frequency: 0.020) from Portuguese and Brazilian individuals or families with MAP/AFAP/FAP (Isidro 2004, Torrezan 2013); however, control chromosomes were not evaluated in these studies. The c.389-1G>C variant was not identified in dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), database MutDB, “Zhejiang Colon Cancer Database”, the ClinVar database, GeneInsight VariantWire database, and COSMIC. The variant was identified in UMD (12x as a Causal variant), with co-occurring pathogenic MUTYH variants (including: c.494A>G and c.1145G>A). The c.389-1G>C variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence and this variant is the type of which could be expected to cause the disorder. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant is classified as pathogenic.

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