rs769237459
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_001048174.2(MUTYH):c.736C>T(p.Arg246Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,461,788 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R246Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001048174.2 missense
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_001128425.2 | c.820C>T | p.Arg274Trp | missense_variant | 10/16 | ENST00000710952.2 | |
MUTYH | NM_001048174.2 | c.736C>T | p.Arg246Trp | missense_variant | 10/16 | ENST00000456914.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000710952.2 | c.820C>T | p.Arg274Trp | missense_variant | 10/16 | NM_001128425.2 | |||
MUTYH | ENST00000456914.7 | c.736C>T | p.Arg246Trp | missense_variant | 10/16 | 1 | NM_001048174.2 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 250086Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135472
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461788Hom.: 0 Cov.: 36 AF XY: 0.0000151 AC XY: 11AN XY: 727188
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 2 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 274 of the MUTYH protein (p.Arg274Trp). This variant is present in population databases (rs769237459, gnomAD 0.003%). This missense change has been observed in individual(s) with MUTYH-associated polyposis (PMID: 16134147, 19032956, 19394335, 19732775; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 449417). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 25820570). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | This missense variant replaces arginine with tryptophan at codon 274 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant was categorized as functionally deficient (PMID: 25820570). This variant has been reported as biallelic with another MUTYH allele in individuals affected with MUTYH-associated polyposis (PMID: 16134147, 19732775, 26511139) and as a single in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 2/250086 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 09, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 18, 2018 | The p.Arg274Trp variant in MUTYH has been reported in the compound heterozygous state at least 2 individuals with MUTYH-associated polyposis (MAP) who had a sec ond pathogenic variant in MUTYH (Aceto 2005, Aretz 2005, Vogt 2009). Additionall y, it segregated with disease in at least one affected family member (Aceto 2005 ). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 449417) and has been identified in 1/33562 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Arg274Trp variant may impact protein function (Komine 2 015); however, these types of assays may not accurately represent biological fun ction. Computational prediction tools and conservation analysis support that the p.Arg274Trp variant may impact the protein. In summary, although additional stu dies are required to fully establish its clinical significance, this variant mee ts criteria to be classified as likely pathogenic for autosomal recessive MAP. A CMG/AMP criteria applied: PM2, PM3, PP1, PP3, PS3_Supporting. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 24, 2019 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 08, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect: defective function in a MutY-deficient E. coli complementation assay (Komine et al., 2015); This variant is associated with the following publications: (PMID: 19032956, 16134147, 28349240, 26976419, 23770606, 19394335, 16557584, 19725997, 26511139, 19732775, 34426522, Feng2021[Abstract], 25820570, 11092888, 11160897) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 22, 2021 | This missense variant replaces arginine with tryptophan at codon 274 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant was categorized as functionally deficient (PMID: 25820570). This variant has been reported as biallelic with another MUTYH allele in individuals affected with MUTYH-associated polyposis (PMID: 16134147, 19732775, 26511139) and as a single in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 2/250086 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 06, 2024 | The p.R274W variant (also known as c.820C>T), located in coding exon 10 of the MUTYH gene, results from a C to T substitution at nucleotide position 820. The arginine at codon 274 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in the literature in a compound heterozygous state with another MUTYH mutation in multiple individuals with adenomatous polyposis and/or GI cancers (Aceto GM et al, J. Exp. Clin. Cancer Res. 2015 ; 34():131; Aceto G et al, Hum. Mutat. 2005 Oct; 26(4):394; Vogt S et al, Gastroenterology 2009 Dec; 137(6):1976-85.e1-10; Aretz S et al. Int. J. Cancer 2006 Aug;119(4):807-14). A functional analysis of this alteration using E. coli complementation, protein stability, and subcellular localization in mammalian cells indicated that this alteration was functionally defective (Komine K et al, Hum. Mutat. 2015 Jul; 36(7):704-11). Of note, this alteration is also designated as p.R260W (c.778C>T) in published literature. Another alteration at the same codon, p.R274Q (c.821G>A), has been detected in conjunction with different pathogenic MUTYH founder mutations in individuals with adenomatous polyposis; however, the phase (whether in cis or trans) is not confirmed (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
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