rs766420907
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1PP5_Very_StrongBS2
The NM_001048174.2(MUTYH):c.1156C>T(p.Gln386Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,794 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001048174.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUTYH | NM_001128425.2 | c.1240C>T | p.Gln414Ter | stop_gained | 13/16 | ENST00000710952.2 | |
MUTYH | NM_001048174.2 | c.1156C>T | p.Gln386Ter | stop_gained | 13/16 | ENST00000456914.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000710952.2 | c.1240C>T | p.Gln414Ter | stop_gained | 13/16 | NM_001128425.2 | |||
MUTYH | ENST00000456914.7 | c.1156C>T | p.Gln386Ter | stop_gained | 13/16 | 1 | NM_001048174.2 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000598 AC: 15AN: 251006Hom.: 2 AF XY: 0.0000589 AC XY: 8AN XY: 135744
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461794Hom.: 2 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727188
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 2 Pathogenic:7
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MUTYH p.Gln414X variant was not identified in the literature nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, COSMIC, MutDB, “Zhejiang Colon Cancer Database”, or ClinVar database. The variant was identified in UMD (5X, but is unvalidated), and in the “InSiGHT Colon Cancer Database”. The p.Gln414X variant leads to a premature stop codon at position 414, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants in the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 16, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change creates a premature translational stop signal (p.Gln414*) 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 (rs766420907, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with polyposis and colorectal cancer (PMID: 27705013). ClinVar contains an entry for this variant (Variation ID: 406824). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 18, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This variant changes 1 nucleotide in exon 13 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 a biallelic individual affected with MUTYH-associated polyposis (PMID: 27705013) and an individual affected with advanced cancer (PMID: 28873162). This variant has been identified in 15/251006 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 | Mendelics | May 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Dec 19, 2022 | A heterozygous nonsense variation in exon 13 of the MUTYH gene that results in a stop codon and premature truncation of the protein at codon 386 (p.Gln386Ter) was detected. This variant has not been reported in the 1000 genomes and gnomAD databases. The in silico predictions of the variant are probably damaging by MutationTaster2 tool. The reference codon is conserved across mammals. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 25, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 27, 2023 | This variant changes 1 nucleotide in exon 13 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 a biallelic individual affected with MUTYH-associated polyposis (PMID: 27705013) and an individual affected with advanced cancer (PMID: 28873162). This variant has been identified in 15/251006 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 | Nov 30, 2022 | The p.Q414* pathogenic mutation (also known as c.1240C>T), located in coding exon 13 of the MUTYH gene, results from a C to T substitution at nucleotide position 1240. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This alteration was reported with another MUTYH gene mutation in a woman diagnosed with adenomatous colon polyposis (15-30 polyps) and colon cancer diagnosed at age 63 (Marabelli M et al. Genet Test Mol Biomarkers 2016 12;20:777-785). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at