rs372267274
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_001048174.2(MUTYH):c.305-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001048174.2 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUTYH | NM_001048174.2 | c.305-1G>C | splice_acceptor_variant | ENST00000456914.7 | |||
MUTYH | NM_001128425.2 | c.389-1G>C | splice_acceptor_variant | ENST00000710952.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000456914.7 | c.305-1G>C | splice_acceptor_variant | 1 | NM_001048174.2 | A1 | |||
MUTYH | ENST00000710952.2 | c.389-1G>C | splice_acceptor_variant | NM_001128425.2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152214Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461894Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2AN XY: 727248
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 2 Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change affects an acceptor splice site in intron 4 of the MUTYH gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 4 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with colorectal polyposis (PMID: 15366000, 17949294, 23561487; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.347-1G>C. ClinVar contains an entry for this variant (Variation ID: 234229). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 5 (Invitae). This variant disrupts a region of the MUTYH protein in which other variant(s) (p.Trp131Arg) have been determined to be pathogenic (PMID: 12853198, 19032956, 19394335, 19732775, 25820570, 26681312; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | Aug 09, 2019 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 26, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 28, 2016 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 29, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | 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 RNA 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: 12853198, 15366000, 17949294, 19032956, 19732775, 19793053, 23561487). 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 24, 2021 | 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). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 01, 2023 | 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 RNA 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: 12853198, 15366000, 17949294, 19032956, 19732775, 19793053, 23561487). 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. - |
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 10, 2022 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 19, 2023 | Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 19725997, 19732775, 17949294, 12853198, 24470512, 15366000, 23561487, 19793053, 19032956, 33084842, 35264596, 33606809) - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 07, 2017 | - - |
Carcinoma of colon Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Neoplasm of stomach;C0206711:Pilomatrixoma;C3272841:Familial adenomatous polyposis 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at