rs786203115
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001048174.2(MUTYH):c.715C>T(p.Gln239Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,792 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 (★★). 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUTYH | NM_001128425.2 | c.799C>T | p.Gln267Ter | stop_gained | 10/16 | ENST00000710952.2 | |
MUTYH | NM_001048174.2 | c.715C>T | p.Gln239Ter | stop_gained | 10/16 | ENST00000456914.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000710952.2 | c.799C>T | p.Gln267Ter | stop_gained | 10/16 | NM_001128425.2 | |||
MUTYH | ENST00000456914.7 | c.715C>T | p.Gln239Ter | stop_gained | 10/16 | 1 | NM_001048174.2 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249998Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135468
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461792Hom.: 0 Cov.: 36 AF XY: 0.00000413 AC XY: 3AN XY: 727194
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 2 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This variant changes 1 nucleotide in exon 10 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 with a second pathogenic variant in an individual affected with MUTYH-associated polyposis (PMID: 31744909). This variant has also been reported in individuals affected with colorectal cancer (PMID: 17703316, 25892863, 32984025), most of whom carried a co-variant. One of these individuals had a sister carrying the same mutations and was affected with polyposis (PMID: 25892863). This variant has been identified in 4/249998 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 | Baylor Genetics | Nov 10, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2023 | This sequence change creates a premature translational stop signal (p.Gln267*) 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 (rs786203115, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and multiple polyposis (PMID: 17703316, 25892863; Invitae). This variant is also known as p.Q253X. ClinVar contains an entry for this variant (Variation ID: 186651). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Dec 10, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 09, 2020 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2021 | The p.Q267* pathogenic mutation (also known as c.799C>T), located in coding exon 10 of the MUTYH gene, results from a C to T substitution at nucleotide position 799. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This alteration was detected in conjunction with another MUTYH mutation in a Korean individual with colon cancer and adenomatous polyposis of the colon (Kim DW et al. Int. J. Colorectal Dis. 2007 Oct;22(10):1173-8). It was also reported in conjunction with another MUTYH mutation in a Chinese patient with colorectal cancer diagnosed at age 40 whose sister had colon polyps at age 46 (Zhang JX et al. World J. Gastroenterol. 2015 Apr;21(14):4136-49). Of note, this alteration is also designated as p.Q253X in published literature. 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 27, 2023 | This variant changes 1 nucleotide in exon 10 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 with a second pathogenic variant in an individual affected with MUTYH-associated polyposis (PMID: 31744909). This variant has also been reported in individuals affected with colorectal cancer (PMID: 17703316, 25892863, 32984025), most of whom carried a co-variant. One of these individuals had a sister carrying the same mutations and was affected with polyposis (PMID: 25892863). This variant has been identified in 4/249998 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. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 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; Observed with a pathogenic MUTYH variant, phase unknown, in patients with a personal history consistent with MUTYH-associated polyposis (Zhang et al., 2015; Li et al., 2020); Also known as MUTYH c.757C>T (p.Gln253Ter); This variant is associated with the following publications: (PMID: 26986879, 25892863, 25525159, 17703316, 25856671, 26963279, 29093764, 31744909, 23605219, 25931827, 35273153, 20663686, 32980694, 34897210, 32973888, 32521533) - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at