rs587780088
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001407075.1(MUTYH):c.-144C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
MUTYH
NM_001407075.1 5_prime_UTR_premature_start_codon_gain
NM_001407075.1 5_prime_UTR_premature_start_codon_gain
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 2.25
Genes affected
MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.386
PP5
Variant 1-45334493-G-A is Pathogenic according to our data. Variant chr1-45334493-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 127845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45334493-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MUTYH | NM_001048174.2 | c.13C>T | p.Arg5* | stop_gained | 2/16 | ENST00000456914.7 | NP_001041639.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000456914.7 | c.13C>T | p.Arg5* | stop_gained | 2/16 | 1 | NM_001048174.2 | ENSP00000407590.2 | ||
ENSG00000288208 | ENST00000671898.1 | n.559C>T | non_coding_transcript_exon_variant | 6/21 | ENSP00000499896.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251478Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135916
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GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461820Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727204
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74314
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 2 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 26, 2023 | This variant changes 1 nucleotide in exon 2 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in the compound heterozygous state in an individual affected with MUTYH-associated polyposis (PMID: 32888815), in biallelic individuals affected with colorectal cancer (PMID: 19732775, 32973888), and in an individual with an unknown second allele affected with colorectal cancer (PMID: 33563768). This variant has also been reported in individuals affected with lung cancer (PMID: 35712480; Wu, et al. poster #230, AACR 2023), renal cell carcinoma (PMID: 33062672), breast cancer (PMID: 33901219), as well as in individuals that participated in genetic screening (PMID: 34428338, 34404389). This variant has been identified in 2/251478 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 26, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | This sequence change creates a premature translational stop signal (p.Arg19*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). This variant is present in population databases (rs587780088, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with adenomatous polyposis and colorectal cancer (PMID: 19394335, 22641385, 24799981). ClinVar contains an entry for this variant (Variation ID: 127845). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 18, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32980694, 31721094, 23035301, 18534194, 19032956, 22641385, 24799981, 19732775, 29330641, 28251689, 27498913, 29625052, 31744909, 32029870, 32888815, 34106356, 31742824, 35273153, 34115236, 20663686, 36988593, 19394335) - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 01, 2023 | This variant changes 1 nucleotide in exon 2 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in the compound heterozygous state in an individual affected with MUTYH-associated polyposis (PMID: 32888815), in biallelic individuals affected with colorectal cancer (PMID: 19732775, 32973888), and in an individual with an unknown second allele affected with colorectal cancer (PMID: 33563768). This variant has also been reported in individuals affected with lung cancer (PMID: 35712480; Wu, et al. poster #230, AACR 2023), renal cell carcinoma (PMID: 33062672), breast cancer (PMID: 33901219), as well as in individuals that participated in genetic screening (PMID: 34428338, 34404389). This variant has been identified in 2/251478 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 28, 2023 | The p.R19* pathogenic mutation (also known as c.55C>T), located in coding exon 2 of the MUTYH gene, results from a C to T substitution at nucleotide position 55. This changes the amino acid from an arginine to a stop codon within coding exon 2. The predicted stop codon occurs within the first 150 nucleotides of the MUTYH gene. This alteration may escape nonsense-mediated mRNA decay and/or be rescued by re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat. Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci. Rep. 2017 May 10;7(1):1653). However, the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in individuals with clinical diagnoses of MUTYH-associated polyposis, including one male diagnosed with colon cancer at age 43 who had 60-70 total colon polyps and co-occurrence with MUTYH c.1147delC (Nielsen M et al. Gastroenterology. 2009 Feb;136:471-6; Jones N et al. Gastroenterology. 2009 Aug;137:489-94; Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85; Li CG et al. J. Gastroenterol. Hepatol. 2017 Oct;32(10):1723-1729). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Carcinoma of colon Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
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 | - - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at