chr1-45333471-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001048174.2(MUTYH):c.206G>A(p.Arg69Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,461,890 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R69G) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
MUTYH
NM_001048174.2 missense
NM_001048174.2 missense
Scores
2
7
10
Clinical Significance
Conservation
PhyloP100: 3.31
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 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.761
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MUTYH | NM_001048174.2 | c.206G>A | p.Arg69Gln | 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.206G>A | p.Arg69Gln | missense_variant | 3/16 | 1 | NM_001048174.2 | ENSP00000407590.2 | ||
| ENSG00000288208 | ENST00000671898.1 | n.794G>A | non_coding_transcript_exon_variant | 7/21 | ENSP00000499896.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251486Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135920
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461890Hom.: 0 Cov.: 35 AF XY: 0.0000371 AC XY: 27AN XY: 727248
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 30, 2022 | The p.Arg97Gln variant in MUTYH has been previously reported in the compound heterozygous state in 1 individual with MUTYH-associated cancers and 1 with breast cancer (Maxwell 2015 PMID: 25503501; Tung 2015 PMD: 25186627). It has also been identified in 0.005% (1/18392) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 185512). Arginine (Arg) at position 97 is not conserved in mammals or evolutionarily distant species, and 4 mammals (Tibetian antelope, cow, sheep, and domestic goat) carry a glutamine (Gln) at this position, raising the possibility that this change may be tolerated. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 03, 2024 | 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; Observed in individuals with breast cancer, colon cancer, and/or colon polyps, as well as unaffected controls (PMID: 25503501, 25186627, 27829682, 33471991, 34250417, 38254803); Also known as R94Q; This variant is associated with the following publications: (PMID: 27829682, 25503501, 25186627, 34426522, 36243179, 25307848, 33471991, 38254803, 34250417) - |
Familial adenomatous polyposis 2 Uncertain:2Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 12, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 29, 2024 | This missense variant replaces arginine with glutamine at codon 97 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer before the age of 50 (PMID: 25186627), an individual affected with early-onset colon cancer and early-onset breast cancer who also carried a second known pathogenic variant in MUTYH (PMID: 25503501), and an individual affected with colorectal neoplasia (PMID: 27829682). This variant has been identified in 3/251486 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 | Baylor Genetics | Feb 19, 2024 | - - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 11, 2023 | Variant summary: MUTYH c.290G>A (p.Arg97Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251486 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.290G>A has been reported in the literature in individuals affected with breast or colorectal cancer as well as unaffected controls (Maxwell_2014, Ricci_2016, Tung_2014, Dorling_2021, Pearlman_2021). These reports 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: 25503501, 25186627, 27829682, 33471991, 34250417). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 20, 2023 | This missense variant replaces arginine with glutamine at codon 97 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer before the age of 50 (PMID: 25186627), an individual affected with early-onset colon cancer and early-onset breast cancer who also carried a second known pathogenic variant in MUTYH (PMID: 25503501), and an individual affected with colorectal neoplasia (PMID: 27829682). This variant has been identified in 3/251486 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 | Ambry Genetics | Mar 21, 2024 | The p.R97Q variant (also known as c.290G>A), located in coding exon 3 of the MUTYH gene, results from a G to A substitution at nucleotide position 290. The arginine at codon 97 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in conjunction with a MUTYH founder mutation (phase unknown) in a patient diagnosed with early-onset colon cancer and bilateral breast cancer, as well as a family history of breast, colon, and uterine cancer, who had previously tested negative for mutations in BRCA1/2 by sequencing (Maxwell KN et al. Genet Med. 2015 Aug;17(8):630-8). This alteration was also detected in an individual diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33) and in 1/299 Italian colorectal cancer patients (Ricci MT et al. J Hum Genet, 2017 Feb;62:309-315). Of note, this alteration is also known as p.R94Q in published literature. This amino acid position is 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. - |
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.Arg97Gln variant was not identified in the literature nor was it identified in the COSMIC, Zhejiang Colon Cancer (LOVD), COGR, or UMD database. The variant was identified in dbSNP (ID: rs755653922) as “With Uncertain significance allele” and the Exome Aggregation Consortium database (August 8, 2016) in 1 of 121384 chromosomes (frequency: 0.000008). The variant was identified in the European (Non-Finnish) population in 1 of 66722 chromosomes (frequency: 0.00001), but not in the African, East Asian, Finnish, Latino, South Asian or Other populations. In Clinvar and Clinvitae, the variant was identified as uncertain significance by Ambry Genetics; InSiGHT Colon Cancer Gene Variant Database (LOVD) 1x as unknown. The p.Arg97 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant amino acid Glutamine (Gln) is present in cow, increasing the likelihood that this variant does not have clinical significance. 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 uncertain significance. - |
Familial cancer of breast Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 08, 2023 | The MUTYH c.290G>A (p.Arg97Gln) missense change has a maximum subpopulation frequency of 0.0054% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer (PMID: 25186627) and colorectal cancer (PMID: 27829682). It was observed to co-occur in unknown phase with a pathogenic MUTYH mutation (p.Gly396Asp) in an individual with a personal history of colorectal cancer and early-onset breast cancer, and a family history of colorectal cancer (PMID: 25503501). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;.;.;.;.;T;.;.;.;T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;T;.;T;T;T;T;T;T;T;T;T
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;.;.;.;.;L;.;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Uncertain
Sift
Benign
D;D;D;D;D;T;D;D;D;T;T;T
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D;T;T
Polyphen
0.52, 0.99, 0.99
.;.;.;.;.;P;D;.;D;.;.;.
Vest4
MutPred
0.57
.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0594);.;.;.;
MVP
MPC
0.28
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at