chr1-45331241-C-T
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP5
The NM_001048174.2(MUTYH):c.1333G>A(p.Ala445Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,614,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A445S) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
MUTYH
NM_001048174.2 missense
NM_001048174.2 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 0.854
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 Uncertain_significance. Variant got 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-45331240-G-T is described in Lovd as [Pathogenic].
PP5
Variant 1-45331241-C-T is Pathogenic according to our data. Variant chr1-45331241-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141614.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=12, Likely_pathogenic=2}.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MUTYH | ENST00000456914.7 | c.1333G>A | p.Ala445Thr | missense_variant | Exon 14 of 16 | 1 | NM_001048174.2 | ENSP00000407590.2 | ||
| ENSG00000288208 | ENST00000671898.1 | n.1921G>A | non_coding_transcript_exon_variant | Exon 18 of 21 | ENSP00000499896.1 |
Frequencies
GnomAD3 genomes 0.0000788 AC: 12AN: 152212Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251492Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135920
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GnomAD4 exome AF: 0.000150 AC: 219AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.000138 AC XY: 100AN XY: 727248
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GnomAD4 genome 0.0000788 AC: 12AN: 152330Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74484
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:12
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 2 Pathogenic:2Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces alanine with threonine at codon 473 of the MUTYH protein. This variant is also known as c.1375G>A (p.Ala459Met) based on an alternative transcript (NM_001048171). 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 strengthen an alternative splice donor site. An RNA study using lymphoblastoid cell lines derived from a phenotypically normal subject has shown that this variant leads to the use of the alternative splice donor site (PMID: 31687339), creating a frameshift in the transcript. The clinical relevance of this observation is not known. A functional study has shown that this variant protein leads to similar base excision repair activity in comparison with the wild-type protein in a bacterial complementation assay (PMID: 25820570). This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754), multiple colorectal adenomas (PMID: 17949294), and breast cancer (PMID: 25186627). This variant has also been identified in 15/282886 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 02, 2025 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 473 of the MUTYH protein (p.Ala473Thr). This variant is present in population databases (rs192816572, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of MUTYH-associated polyposis (PMID: 14991577, 17949294; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1375G>A (p.A459T). ClinVar contains an entry for this variant (Variation ID: 141614). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect MUTYH function (PMID: 25820570). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 19, 2024 | Variant summary: MUTYH c.1417G>A (p.Ala473Thr) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) and Adenine DNA glycosylase, C-terminal domain (IPR029119) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic 5' splicing donor site. At least one publication reports experimental evidence supporting computational predictions that this variant affects mRNA splicing, finding that the variant resulted in the utilization of a cryptic 5' donor site, leading to a frameshift (p.Ala473PhefsX38; Yamada_2019). This finding was largely corroborated by RNA analysis performed at our partner laboratory. The variant allele was found at a frequency of 5.2e-05 in 251686 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (5.2e-05 vs 0.0046), allowing no conclusion about variant significance. c.1417G>A has been reported in the literature in individuals affected with colorectal, breast, and cervical cancer, however without strong evidence for causality (e.g., Fleischmann_2004, Olschwang_2007, Tung_2014, Yurgelun_2015, Barreiro_2022). It has however, been observed in trans with other pathogenic alleles in at-least two individuals affected with features of MUTYH-Associated Polyposis at our laboratory (Internal data). These data indicate that the variant is likely to be associated with disease. At least one publication reports in-vitro experimental evidence evaluating an impact on protein function by E-coli base excision repair. These results showed no damaging effect of this variant (Komine_2015). The following publications have been ascertained in the context of this evaluation (PMID: 16134146, 34816434, 14991577, 25820570, 26332594, 17949294, 25186627, 31687339, 25980754). ClinVar contains an entry for this variant (Variation ID: 141614). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 25, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 07, 2024 | - - |
not provided Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 19, 2023 | Published functional studies demonstrate normal base excision repair activity, but this variant may result in aberrant splicing (Komine et al., 2015; Yamada et al., 2019); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14991577, 25980754, 27498913, 17949294, 26332594, 16134146, 26269718, 19725997, 25186627, 31687339, 17031395, 25820570, 23108399, 15465463, 34816434) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 27, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 28, 2024 | The MUTYH c.1417G>A (p.Ala473Thr) variant has been reported in the published literature in individuals affected with colorectal cancer and/or polyps (PMIDs: 25980754 (2015), 17949294 (2007), 14991577 (2004)), and breast cancer (PMID: 25186627 (2015)). Experimental studies regarding the variant's impact on protein function report inconclusive findings as to whether or not this variant is damaging (PMIDs: 31687339 (2019), 25820570 (2015)). The frequency of this variant in the general population, 0.0002 (10/50820 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 conflicting predictions that this variant is deleterious or benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on MUTYH mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, we are unable to determine the clinical significance of this variant. - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 15, 2019 | Variant classified as Uncertain Significance - Favor Benign. The p.Ala473Thr var iant in MUTYH has been reported in the heterozygous state in one individual with colorectal cancer (Fleischmann 2004) and one individual who was tested for a Ly nch Syndrome-associated cancer or colorectal polyps (Yurgelun 2015). Another stu dy reported this variant in an unspecified number of individuals with adenomatou s polyposis (Olschwang 2007; variant reported as Ala459Thr). In vitro functional studies provide some evidence that the p.Ala473Thr variant may not impact prote in function (Komine 2015). However, these types of assays may not accurately rep resent biological function. This variant has also been reported in ClinVar (Vari ation ID 141614) and in 0.02% (14/129192) of European chromosomes by gnomAD (htt p://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis support that the p.Ala473Thr variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary , while the clinical significance of the p.Ala473Thr variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP criteria applied: BP 4, BS3_P. - |
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 18, 2024 | The p.A473T variant (also known as c.1417G>A), located in coding exon 14 of the MUTYH gene, results from a G to A substitution at nucleotide position 1417. The alanine at codon 473 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in several patient cohorts including an early-onset colorectal cancer patient, an individual with greater than 5 colorectal adenomas, and an individual who underwent clinical genetic testing for Lynch syndrome; however, no other alterations in the MUTYH gene were detected in these cases, and p.A473T was classified as a variant of unknown significance (Fleischmann C et al. Int. J. Cancer. 2004 Apr;109:554-8; Olschwang S et al. Genet. Test. 2007;11:315-20; Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). Functional studies of this variant demonstrate that it has near-wild type function in an E. coli-based complementation assay; however, glycosylase assays have never been conducted on this variant (Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). Of note, this alteration is also designated as p.A459T in published literature. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 22, 2023 | This missense variant replaces alanine with threonine at codon 473 of the MUTYH protein. This variant is also known as c.1375G>A (p.Ala459Met) based on an alternative transcript (NM_001048171). 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 strengthen an alternative splice donor site. An RNA study using lymphoblastoid cell lines derived from a phenotypically normal subject has shown that this variant leads to the use of the alternative splice donor site (PMID: 31687339), creating a frameshift in the transcript. The clinical relevance of this observation is not known. A functional study has shown that this variant protein leads to similar base excision repair activity in comparison with the wild-type protein in a bacterial complementation assay (PMID: 25820570). This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754), multiple colorectal adenomas (PMID: 17949294), and breast cancer (PMID: 25186627). This variant has also been identified in 15/282886 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Gastric cancer;C3272841:Familial adenomatous polyposis 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 20, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
.;.;.;.;.;.;T;.;.;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
.;.;T;.;T;T;T;T;T;T;T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N;N;N;.
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;T;T;T;T;T;T;.
Sift4G
Benign
T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.043, 0.22, 0.14
.;.;.;.;.;.;B;B;.;.;B;.
Vest4
MVP
MPC
0.12
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at