Variant summary: MUTYH c.1420C>T (p.Arg474Cys) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) and 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. The variant allele was found at a frequency of 5.2e-05 in 251490 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (5.2e-05 vs 0.0046), allowing no conclusion about variant significance. c.1420C>T has been reported in the literature in individuals affected with atherosclerosis, colorectal cancer and pancreatic ductal adenocarcinoma (Johnston_2012, Yurgelun_2017, Singhi_2019). These reports however, 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. Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.1336C>T (p.Arg446Cys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(13)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance
13
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001048174.2(MUTYH):c.1336C>T (p.Arg446Cys)
Variation ID: 41754 Accession: VCV000041754.29
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p34.1 1: 45331238 (GRCh38) [ NCBI UCSC ] 1: 45796910 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 12, 2013 Nov 3, 2024 Sep 27, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001048174.2:c.1336C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Arg446Cys missense NM_001128425.2:c.1420C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Arg474Cys missense NM_001048171.2:c.1336C>T NP_001041636.2:p.Arg446Cys missense NM_001048172.2:c.1339C>T NP_001041637.1:p.Arg447Cys missense NM_001048173.2:c.1336C>T NP_001041638.1:p.Arg446Cys missense NM_001293190.2:c.1381C>T NP_001280119.1:p.Arg461Cys missense NM_001293191.2:c.1369C>T NP_001280120.1:p.Arg457Cys missense NM_001293192.2:c.1060C>T NP_001280121.1:p.Arg354Cys missense NM_001293195.2:c.1336C>T NP_001280124.1:p.Arg446Cys missense NM_001293196.2:c.1060C>T NP_001280125.1:p.Arg354Cys missense NM_001350650.2:c.991C>T NP_001337579.1:p.Arg331Cys missense NM_001350651.2:c.991C>T NP_001337580.1:p.Arg331Cys missense NM_012222.3:c.1411C>T NP_036354.1:p.Arg471Cys missense NR_146882.2:n.1564C>T non-coding transcript variant NR_146883.2:n.1413C>T non-coding transcript variant NC_000001.11:g.45331238G>A NC_000001.10:g.45796910G>A NG_008189.1:g.14233C>T LRG_220:g.14233C>T LRG_220t1:c.1420C>T LRG_220p1:p.Arg474Cys - Protein change
- R474C, R460C, R354C, R331C, R457C, R446C, R447C, R461C, R471C
- Other names
- -
- Canonical SPDI
- NC_000001.11:45331237:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| MUTYH | - | - |
GRCh38 GRCh37 |
2689 | 2845 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 27, 2024 | RCV000034671.6 | |
| Uncertain significance (1) |
no assertion criteria provided
|
Jul 24, 2014 | RCV000144638.1 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 12, 2024 | RCV000164389.13 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 23, 2017 | RCV000515389.2 | |
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 11, 2024 | RCV000206141.17 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 3, 2020 | RCV000780500.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Aug 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917805.2
First in ClinVar: Jun 02, 2019 Last updated: Sep 14, 2020 |
Comment:
Variant summary: MUTYH c.1420C>T (p.Arg474Cys) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) and C-terminal domain (IPR029119) of the … (more)
Variant summary: MUTYH c.1420C>T (p.Arg474Cys) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) and 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. The variant allele was found at a frequency of 5.2e-05 in 251490 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (5.2e-05 vs 0.0046), allowing no conclusion about variant significance. c.1420C>T has been reported in the literature in individuals affected with atherosclerosis, colorectal cancer and pancreatic ductal adenocarcinoma (Johnston_2012, Yurgelun_2017, Singhi_2019). These reports however, 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. Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
|
Uncertain significance
(May 23, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Pilomatrixoma
Familial adenomatous polyposis 2 Gastric cancer
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611406.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
|
|
|
Uncertain significance
(Oct 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004198820.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Uncertain significance
(Dec 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000259566.12
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 474 of the MUTYH protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 474 of the MUTYH protein (p.Arg474Cys). This variant is present in population databases (rs200229669, gnomAD 0.009%). This missense change has been observed in individual(s) with bilateral breast cancer and colorectal cancer (PMID: 28135145, 32854451). This variant is also known as c.1378C>T (p.Arg460Cys). ClinVar contains an entry for this variant (Variation ID: 41754). 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. 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. (less)
|
|
|
Uncertain significance
(Dec 10, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000487322.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
|
|
|
Uncertain significance
(Jun 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888309.3
First in ClinVar: Apr 12, 2013 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with colorectal cancer (PMID: 28135145 (2017), 28944238 (2017), 35668106 (2022)), and breast cancer (PMID: … (more)
In the published literature, this variant has been reported in individuals with colorectal cancer (PMID: 28135145 (2017), 28944238 (2017), 35668106 (2022)), and breast cancer (PMID: 32854451 (2020), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). This variant has also been reported in unaffected individuals (PMID: 30267214 (2018), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). The frequency of this variant in the general population, 0.00026 (3/11610 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. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Uncertain significance
(Aug 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000685574.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 474 of the MUTYH protein. This variant is also known as c.1378C>T (p.Arg460Cys) based on an … (more)
This missense variant replaces arginine with cysteine at codon 474 of the MUTYH protein. This variant is also known as c.1378C>T (p.Arg460Cys) 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 28135145, 35668106), bilateral breast cancer (PMID: 32854451) and pancreatic cancer (PMID: 30836094). This variant has also been identified in 14/282888 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. (less)
|
|
|
Uncertain Significance
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004825680.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces arginine with cysteine at codon 474 of the MUTYH protein. This variant is also known as c.1378C>T (p.Arg460Cys) based on an … (more)
This missense variant replaces arginine with cysteine at codon 474 of the MUTYH protein. This variant is also known as c.1378C>T (p.Arg460Cys) 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 28135145, 35668106), bilateral breast cancer (PMID: 32854451) and pancreatic cancer (PMID: 30836094). This variant has also been identified in 14/282888 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. (less)
Number of individuals with the variant: 18
|
|
|
Uncertain significance
(Sep 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000215025.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.R474C variant (also known as c.1420C>T), located in coding exon 14 of the MUTYH gene, results from a C to T substitution at nucleotide … (more)
The p.R474C variant (also known as c.1420C>T), located in coding exon 14 of the MUTYH gene, results from a C to T substitution at nucleotide position 1420. The arginine at codon 474 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in 1/572 cancer-free atherosclerosis patients (Johnston JJ et al. Am. J. Hum. Genet. 2012 Jul;91:97-108). In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in two control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This variant was also reported in a cohort study of colorectal patients that also included a control group (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This variant was identified in the germline along with MUTYH c.603G>T (p.M201I) in a patient in the 80-89 year old age group with colorectal cancer (Georgeson P et al. Nat Commun, 2022 06;13:3254). In a multi-gene panel study of patients with bilateral breast cancer, this variant was observed in 1/139 cases (Fanale D et al. Cancers (Basel), 2020 Aug;12:). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Mar 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV005045447.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
|
|
|
Uncertain significance
(Sep 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000293927.13
First in ClinVar: Apr 12, 2013 Last updated: Nov 03, 2024 |
Comment:
Observed in individuals with colorectal cancer and breast cancer, and also in unaffected controls (PMID: 28135145, 32854451, 35668106, 30267214, 28944238, 33471991); Not observed at significant … (more)
Observed in individuals with colorectal cancer and breast cancer, and also in unaffected controls (PMID: 28135145, 32854451, 35668106, 30267214, 28944238, 33471991); 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; This variant is associated with the following publications: (PMID: 22722201, 22703879, 32854451, 28135145, 35668106, 30267214, 28944238, 33471991, 30836094, 27600092, 23108399) (less)
|
|
|
Uncertain significance
(Jul 24, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Carcinoma of colon
Affected status: unknown
Allele origin:
germline
|
Pathway Genomics
Accession: SCV000189965.1
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
|
|
|
variant of unknown significance
(Jul 13, 2012)
|
no assertion criteria provided
Method: research
|
not provided
Affected status: no
Allele origin:
germline
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043367.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Uncertain significance.
Number of individuals with the variant: 1
Comment on evidence:
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
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Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 474 of the MUTYH protein (p.Arg474Cys). This variant is present in population databases (rs200229669, gnomAD 0.009%). This missense change has been observed in individual(s) with bilateral breast cancer and colorectal cancer (PMID: 28135145, 32854451). This variant is also known as c.1378C>T (p.Arg460Cys). ClinVar contains an entry for this variant (Variation ID: 41754). 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. 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.
Comment:
In the published literature, this variant has been reported in individuals with colorectal cancer (PMID: 28135145 (2017), 28944238 (2017), 35668106 (2022)), and breast cancer (PMID: 32854451 (2020), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). This variant has also been reported in unaffected individuals (PMID: 30267214 (2018), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). The frequency of this variant in the general population, 0.00026 (3/11610 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. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This missense variant replaces arginine with cysteine at codon 474 of the MUTYH protein. This variant is also known as c.1378C>T (p.Arg460Cys) 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 28135145, 35668106), bilateral breast cancer (PMID: 32854451) and pancreatic cancer (PMID: 30836094). This variant has also been identified in 14/282888 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.
Comment:
This missense variant replaces arginine with cysteine at codon 474 of the MUTYH protein. This variant is also known as c.1378C>T (p.Arg460Cys) 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 28135145, 35668106), bilateral breast cancer (PMID: 32854451) and pancreatic cancer (PMID: 30836094). This variant has also been identified in 14/282888 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.
Comment:
The p.R474C variant (also known as c.1420C>T), located in coding exon 14 of the MUTYH gene, results from a C to T substitution at nucleotide position 1420. The arginine at codon 474 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in 1/572 cancer-free atherosclerosis patients (Johnston JJ et al. Am. J. Hum. Genet. 2012 Jul;91:97-108). In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in two control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This variant was also reported in a cohort study of colorectal patients that also included a control group (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This variant was identified in the germline along with MUTYH c.603G>T (p.M201I) in a patient in the 80-89 year old age group with colorectal cancer (Georgeson P et al. Nat Commun, 2022 06;13:3254). In a multi-gene panel study of patients with bilateral breast cancer, this variant was observed in 1/139 cases (Fanale D et al. Cancers (Basel), 2020 Aug;12:). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Observed in individuals with colorectal cancer and breast cancer, and also in unaffected controls (PMID: 28135145, 32854451, 35668106, 30267214, 28944238, 33471991); 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; This variant is associated with the following publications: (PMID: 22722201, 22703879, 32854451, 28135145, 35668106, 30267214, 28944238, 33471991, 30836094, 27600092, 23108399)
Comment:
Converted during submission to Uncertain significance.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: MUTYH c.1420C>T (p.Arg474Cys) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) and 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. The variant allele was found at a frequency of 5.2e-05 in 251490 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (5.2e-05 vs 0.0046), allowing no conclusion about variant significance. c.1420C>T has been reported in the literature in individuals affected with atherosclerosis, colorectal cancer and pancreatic ductal adenocarcinoma (Johnston_2012, Yurgelun_2017, Singhi_2019). These reports however, 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. Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 474 of the MUTYH protein (p.Arg474Cys). This variant is present in population databases (rs200229669, gnomAD 0.009%). This missense change has been observed in individual(s) with bilateral breast cancer and colorectal cancer (PMID: 28135145, 32854451). This variant is also known as c.1378C>T (p.Arg460Cys). ClinVar contains an entry for this variant (Variation ID: 41754). 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. 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.
Comment:
In the published literature, this variant has been reported in individuals with colorectal cancer (PMID: 28135145 (2017), 28944238 (2017), 35668106 (2022)), and breast cancer (PMID: 32854451 (2020), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). This variant has also been reported in unaffected individuals (PMID: 30267214 (2018), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). The frequency of this variant in the general population, 0.00026 (3/11610 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. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This missense variant replaces arginine with cysteine at codon 474 of the MUTYH protein. This variant is also known as c.1378C>T (p.Arg460Cys) 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 28135145, 35668106), bilateral breast cancer (PMID: 32854451) and pancreatic cancer (PMID: 30836094). This variant has also been identified in 14/282888 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.
Comment:
This missense variant replaces arginine with cysteine at codon 474 of the MUTYH protein. This variant is also known as c.1378C>T (p.Arg460Cys) 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 28135145, 35668106), bilateral breast cancer (PMID: 32854451) and pancreatic cancer (PMID: 30836094). This variant has also been identified in 14/282888 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.
Comment:
The p.R474C variant (also known as c.1420C>T), located in coding exon 14 of the MUTYH gene, results from a C to T substitution at nucleotide position 1420. The arginine at codon 474 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in 1/572 cancer-free atherosclerosis patients (Johnston JJ et al. Am. J. Hum. Genet. 2012 Jul;91:97-108). In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in two control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This variant was also reported in a cohort study of colorectal patients that also included a control group (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This variant was identified in the germline along with MUTYH c.603G>T (p.M201I) in a patient in the 80-89 year old age group with colorectal cancer (Georgeson P et al. Nat Commun, 2022 06;13:3254). In a multi-gene panel study of patients with bilateral breast cancer, this variant was observed in 1/139 cases (Fanale D et al. Cancers (Basel), 2020 Aug;12:). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Observed in individuals with colorectal cancer and breast cancer, and also in unaffected controls (PMID: 28135145, 32854451, 35668106, 30267214, 28944238, 33471991); 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; This variant is associated with the following publications: (PMID: 22722201, 22703879, 32854451, 28135145, 35668106, 30267214, 28944238, 33471991, 30836094, 27600092, 23108399)
Comment:
Converted during submission to Uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures. | Georgeson P | Nature communications | 2022 | PMID: 35668106 |
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
| Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2. | Fanale D | Cancers | 2020 | PMID: 32854451 |
| Real-Time Targeted Genome Profile Analysis of Pancreatic Ductal Adenocarcinomas Identifies Genetic Alterations That Might Be Targeted With Existing Drugs or Used as Biomarkers. | Singhi AD | Gastroenterology | 2019 | PMID: 30836094 |
| Rare loss of function variants in candidate genes and risk of colorectal cancer. | Rosenthal EA | Human genetics | 2018 | PMID: 30267214 |
| Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. | DeRycke MS | Molecular genetics & genomic medicine | 2017 | PMID: 28944238 |
| Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
| Actionable Genes, Core Databases, and Locus-Specific Databases. | Pinard A | Human mutation | 2016 | PMID: 27600092 |
| The landscape of cancer genes and mutational processes in breast cancer. | Stephens PJ | Nature | 2012 | PMID: 22722201 |
| Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. | Johnston JJ | American journal of human genetics | 2012 | PMID: 22703879 |
Text-mined citations for rs200229669 ...
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Record last updated Nov 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.