rs765123255
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001293192.2(MUTYH):c.-36C>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 0.0000328 in 1,614,090 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 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
MUTYH
NM_001293192.2 5_prime_UTR_premature_start_codon_gain
NM_001293192.2 5_prime_UTR_premature_start_codon_gain
Scores
13
4
2
Clinical Significance
Conservation
PhyloP100: 3.27
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 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.966
PP5
Variant 1-45333436-G-A is Pathogenic according to our data. Variant chr1-45333436-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45333436-G-A is described in Lovd as [Pathogenic]. Variant chr1-45333436-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MUTYH | NM_001048174.2 | c.241C>T | p.Arg81Trp | missense_variant | 3/16 | ENST00000456914.7 | NP_001041639.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MUTYH | ENST00000456914.7 | c.241C>T | p.Arg81Trp | missense_variant | 3/16 | 1 | NM_001048174.2 | ENSP00000407590.2 | ||
| ENSG00000288208 | ENST00000671898.1 | n.829C>T | non_coding_transcript_exon_variant | 7/21 | ENSP00000499896.1 |
Frequencies
GnomAD3 genomes 0.0000460 AC: 7AN: 152202Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251476Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135912
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GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461888Hom.: 0 Cov.: 35 AF XY: 0.0000344 AC XY: 25AN XY: 727244
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GnomAD4 genome 0.0000460 AC: 7AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74350
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 2 Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 109 of the MUTYH protein (p.Arg109Trp). This variant is present in population databases (rs765123255, gnomAD 0.006%). This missense change has been observed in individual(s) with early-onset colorectal cancer, MUTYH-associated polyposis, and/or suspected Lynch syndrome (PMID: 19732775, 21520333, 24799981, 25980754). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 183896). 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: 24799981). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 01, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Mar 30, 2016 | The c.325C>T (p.Arg109Trp) missense variant in the MUTYH gene has been previously reported in multiple individuals affected with Familial Adenomatous Polyposis (Vogt et al., 2009; Shinmura et al., 2014; Nielsen M et al., 2009). In two unrelated individuals, this variant was observed in trans with a known pathogenic variant, Gly396Asp (Vogt et al., 2009; Yurgelun MB et al., 2015). Furthermore, an in vitro functional assay demonstrated that this variant resulted in reduced DNA glycosylase activity and impaired mutation-suppression activity (Shinmura et al., 2014). This variant is reported at low frequency in the population databases (Exome Sequencing Project = NA; 1000 Genomes = NA; and ExAC = 0.006%). Multiple in silico algorithms predict this variant to have a deleterious effect (CADD = 15.47; PolyPhen = 1.0; SIFT = 0.0). Ambry Genetics has classified this variant as Likely pathogenic. Therefore, this collective evidence supports the classification of the c.325C>T (p.Arg109Trp) as a recessive Likely pathogenic variant for Familial Adenomatous Polyposis. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 16, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 18, 2015 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2024 | Observed in the apparently heterozygous state in individuals with Lynch syndrome-associated cancers and/or colon polyps, as well as other cancers (PMID: 17949294, 25980754, 35264596, 34308104); Published functional studies demonstrate a damaging effect: decreased DNA glycosylase activity, decreased ability to suppress 8-hydroxyguanine-induced mutations compared to wild type (PMID: 24799981); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.283C>T, Arg95Trp, and R81W; This variant is associated with the following publications: (PMID: 20725929, 28152038, 19732775, 19032956, 24799981, 17949294, 25980754, 26600934, 26694661, 21520333, 27253753, 19394335, 30604180, 33830941, 34308104, 35264596, 30291343, 32980694) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 18, 2024 | The MUTYH c.325C>T (p.Arg109Trp) variant has been reported in the published literature as compound heterozygous with a pathogenic MUTYH variant in individuals with MUTYH-associated polyposis (PMIDs: 27705013 (2016), 27145315 (2016), 25980754 (2015), 19732775 (2009), 19527492 (2009), 19394335 (2009)). It was also mentioned in an individual with suspected Lynch syndrome (25980754 (2015)), urothelial cancer (PMID: 31844177 (2020)) and as heterozygous in an individual with early onset colorectal cancer (PMID: 24799981 (2014)). This variant was also reported in breast cancer cases as well as in reportedly healthy individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). A functional study demonstrated that this variant has impaired DNA repair activity in vitro (PMID: 24799981 (2014)). The frequency of this variant in the general population, 0.000054 (7/129178 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 25, 2022 | The p.R109W variant (also known as c.325C>T), located in coding exon 3 of the MUTYH gene, results from a C to T substitution at nucleotide position 325. The arginine at codon 109 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been identified, in conjunction with a pathogenic MUTYH mutation, in multiple patients with colorectal cancer and/or polyposis (Vogt et al. Gastroenterology. 2009;137:1976–1985; Yurgelun MB et al. Gastroenterology 2015 Sep;149:604-13.e20; Church J et al. Dis. Colon Rectum, 2016 Jun;59:565; Ambry internal data). This alteration was also identified in 1 of 34 patients with colorectal cancer under age 43 from a cohort of 685 Japanese patients and was associated with severely reduced MUTYH protein function (Shinmura K et al. Oxid Med Cell Longev 2014;2014:617351). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 10, 2023 | This missense variant replaces arginine with tryptophan at codon 109 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant disrupts the DNA glycosylase activity of the MUTYH protein and its ability to suppress mutations (PMID: 24799981). This variant has been reported in the compound heterozygous state in individuals affected with MUTYH-associated polyposis and colorectal cancer (PMID: 19394335, 19527492, 19732775; ClinVar SCV000517270.5) and in an individual suspected of having Lynch syndrome (PMID: 25980754). This variant has also been observed in a heterozygous individual affected with early-onset colorectal cancer (PMID: 24799981). This variant has been identified in 11/282856 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Carcinoma of colon Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Arg109Trp variant was identified in 2 of 438 proband chromosomes (frequency: 0.005) from Euorpean and Japanese individuals or families with MAP or early onset colorectal cancer (Nielsen 2009, Shinmura 2014); The variant was not identified in dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), MutDB, “Zhejiang Colon Cancer Database”, the ClinVar database, GeneInsight VariantWire database, UMD and COSMIC; nor was it previously identified in our laboratory. The variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 6 of 121394 chromosomes (all heterozygotes; frequency: 4.94E-05) from a population of European (Non-Finnish) (4/66728 individuals) and South Asian (2/16512) individuals, but not in East Asian, African, Latino or European (Finnish) individuals; the variant was also identified in the InSiGHT Colon Cancer Gene Variant Database (3x) and HGMD. The p.Arg109 residue is conserved across mammals and lower organisms, and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Trp (Tryptophan) variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The p.Arg109Trp variant was identified in a Japanese early onset CRC patient (heterozygous germline, and not biallelic for MUTYH), and studies using DNA cleavage and supF forward mutation assays showed functional impairment through defective DNA glycosylase activity and impaired suppressive activity against mutations (Shinmura 2014). In a Dutch study evaluating histological and molecular aspects of MAP tumours, it was found that these tumours show similarities to sporadic and Lynch tumors. The variant co-occurred with the pathogenic p.Gly396Asp (Nielsen 2009). An additional European study looking at incidence of both malignant and benign extracolonic lesions in MAP patients, the variant co-occurred with the pathogenic p.Gly396Asp. (Vogt 2009) increasing the likelihood this variant is clinically significant. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic. - |
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
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;.;.;.;.;D;.;.;.;T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D;.;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;.;.;H;.;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;.;.;D;D;.;D;.;.;.
Vest4
MVP
MPC
0.56
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
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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