1-45331265-G-C
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001048174.2(MUTYH):c.1309C>G(p.Pro437Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P437L) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000070 ( 0 hom. )
Consequence
MUTYH
NM_001048174.2 missense
NM_001048174.2 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 2.80
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 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.14406195).
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MUTYH | ENST00000456914.7 | c.1309C>G | p.Pro437Ala | missense_variant | 14/16 | 1 | NM_001048174.2 | ENSP00000407590.2 | ||
| ENSG00000288208 | ENST00000671898.1 | n.1897C>G | non_coding_transcript_exon_variant | 18/21 | ENSP00000499896.1 |
Frequencies
GnomAD3 genomes 0.0000394 AC: 6AN: 152130Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251494Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135922
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GnomAD4 exome AF: 0.0000705 AC: 103AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 49AN XY: 727244
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GnomAD4 genome 0.0000394 AC: 6AN: 152130Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74324
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jun 29, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 13, 2023 | In the published literature, this variant has been reported in affected individuals with colorectal cancer (PMID: 28135145 (2017) and 34326862 (2021)) and in an individual with hereditary mixed polyposis syndrome who also had a pathogenic GREM1 duplication (PMID: 26947005 (2016)). It has also been reported in individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)), as well as in controls (PMIDs: 30267214 (2018) and 33471991 (2021)). The frequency of this variant in the general population, 0.00014 (18/129178 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 22, 2024 | Reported in the heterozygous state in individuals with colorectal cancer or polyposis; however, a pathogenic duplication in SCG5/GREM1 was also identified in the polyposis case (PMID: 26947005, 28135145); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(Pro451Ala); This variant is associated with the following publications: (PMID: 28135145, 26947005, 23108399, 34326862, 37937776) - |
Familial adenomatous polyposis 2 Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 09, 2024 | This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 465 of the MUTYH protein (p.Pro465Ala). This variant is present in population databases (rs375597447, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). This variant is also known as c.1351C>G (p.P451A). ClinVar contains an entry for this variant (Variation ID: 141925). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 27, 2024 | This missense variant replaces proline with alanine at codon 465 of the MUTYH protein. This variant is also known as c.1351C>G (p.Pro451Ala) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145) and in a family affected with hereditary polyposis, where the disease segregated with a pathogenic duplication of the GREM1 gene enhancer region (PMID: 26947005). This variant has been identified in 19/282872 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 29, 2016 | - - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 07, 2024 | Variant summary: MUTYH c.1393C>G (p.Pro465Ala) results in a non-conservative amino acid change located in the MutY, C-terminal domain (IPR029119) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251494 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (6.8e-05 vs 0.0046), allowing no conclusion about variant significance. c.1393C>G has been reported in the literature in individuals affected with colorectal cancer and/or polyposis, and breast cancer (Ziai_2016, Yurgelun_2017, Bhai_2021). In one of these reports this MUTYH variant was not the cause of disease as a different pathogenic variant, namely a 40 kb duplication upstream of the GREM1 gene segregated with the hereditary mixed polyposis syndrome (HMPS) phenotype (Ziai_2016). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 28135145, 26947005). ClinVar contains an entry for this variant (Variation ID: 141925). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 28, 2022 | The p.P465A variant (also known as c.1393C>G), located in coding exon 14 of the MUTYH gene, results from a C to G substitution at nucleotide position 1393. The proline at codon 465 is replaced by alanine, an amino acid with highly similar properties. This alteration was reported as a variant of uncertain significance identified in a cohort of 1058 colorectal cancer patients who underwent multi-gene panel testing and were unselected for age of diagnosis, family history, or MSI/MMR status (Yurgelun MB et al J. Clin. Oncol. 2017 Apr;35:1086-1095). This variant was also detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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 proline with alanine at codon 465 of the MUTYH protein. This variant is also known as c.1351C>G (p.Pro451Ala) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145) and in a family affected with hereditary polyposis, where the disease segregated with a pathogenic duplication of the GREM1 gene enhancer region (PMID: 26947005). This variant has been identified in 19/282872 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. - |
Carcinoma of colon Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MUTYH p.Pro465Ala variant was not identified in the literature, nor was it identified in dbSNP, HGMD, “InSiGHT Colon Cancer Database”, or the COSMIC database. The variant was identified in the NHLBI Exome Sequencing Project, with a frequency of 0.0001 in European American alleles; however, this frequency is based on one occurrence of the variant allele in 8600 alleles tested. The p.Pro465 residue is conserved in mammals but not across lower organisms, and the variant amino acid Alanine (Ala) is present in chicken, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. - |
Gastric cancer;C3272841:Familial adenomatous polyposis 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 22, 2024 | - - |
Retinoblastoma Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 21, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
.;.;.;.;.;.;T;.;.;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;D;.;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N;N;N;.
REVEL
Benign
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
0.0
.;.;.;.;.;.;B;B;.;.;B;.
Vest4
MVP
MPC
0.11
ClinPred
T
GERP RS
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gMVP
Splicing
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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