ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.1463C>T (p.Pro488Leu)
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.
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(5); Benign(2); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001048174.2(MUTYH):c.1463C>T (p.Pro488Leu)
Variation ID: 134867 Accession: VCV000134867.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45329409 (GRCh38) [ NCBI UCSC ] 1: 45795081 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 9, 2014 May 1, 2024 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001048174.2:c.1463C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Pro488Leu missense NM_001128425.2:c.1547C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Pro516Leu missense NM_001048171.2:c.1463C>T NP_001041636.2:p.Pro488Leu missense NM_001048172.2:c.1466C>T NP_001041637.1:p.Pro489Leu missense NM_001048173.2:c.1463C>T NP_001041638.1:p.Pro488Leu missense NM_001293190.2:c.1508C>T NP_001280119.1:p.Pro503Leu missense NM_001293191.2:c.1496C>T NP_001280120.1:p.Pro499Leu missense NM_001293192.2:c.1187C>T NP_001280121.1:p.Pro396Leu missense NM_001293195.2:c.1463C>T NP_001280124.1:p.Pro488Leu missense NM_001293196.2:c.1187C>T NP_001280125.1:p.Pro396Leu missense NM_001350650.2:c.1118C>T NP_001337579.1:p.Pro373Leu missense NM_001350651.2:c.1118C>T NP_001337580.1:p.Pro373Leu missense NM_012222.3:c.1538C>T NP_036354.1:p.Pro513Leu missense NR_146882.2:n.1871C>T non-coding transcript variant NR_146883.2:n.1720C>T non-coding transcript variant NC_000001.11:g.45329409G>A NC_000001.10:g.45795081G>A NG_008189.1:g.16062C>T LRG_220:g.16062C>T LRG_220t1:c.1547C>T LRG_220p1:p.Pro516Leu - Protein change
- P516L, P373L, P488L, P499L, P503L, P396L, P489L, P513L
- Other names
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- Canonical SPDI
- NC_000001.11:45329408:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
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 | ||
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HI score
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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. |
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MUTYH | - | - |
GRCh38 GRCh37 |
2643 | 2796 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely benign (2) |
criteria provided, single submitter
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Jan 30, 2021 | RCV000121602.8 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Sep 20, 2021 | RCV000131522.13 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 26, 2024 | RCV000457983.13 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 25, 2017 | RCV000656914.5 |
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. |
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Benign
(Mar 14, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000903067.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Uncertain significance
(Jan 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000545757.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 516 of the MUTYH protein (p.Pro516Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 516 of the MUTYH protein (p.Pro516Leu). This variant is present in population databases (rs587778542, gnomAD 0.004%). This missense change has been observed in individual(s) with attenuated familial adenomatous polyposis (PMID: 20618354). This variant is also known as p.P502L. ClinVar contains an entry for this variant (Variation ID: 134867). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect MUTYH function (PMID: 25820570, 26377631). 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)
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Uncertain significance
(Apr 09, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000226446.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Apr 25, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000292632.11
First in ClinVar: Jul 24, 2016 Last updated: Dec 15, 2018 |
Comment:
This variant is denoted MUTYH c.1547C>T at the cDNA level, p.Pro516Leu (P516L) at the protein level, and results in the change of a Proline to … (more)
This variant is denoted MUTYH c.1547C>T at the cDNA level, p.Pro516Leu (P516L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant, previously reported as MYH 1505C>T (P502L) using an alternate reference sequence, has been observed in at least one individual with colon adenomas as well as in two healthy controls (Fleischmann 2004, Al-Tassan 2004, Morak 2010). In functional studies, this variant showed complementation of functional deficiency, DNA binding, and glycosylase activity similar to wild-type, but reduced binding to protein partner PCNA (Brinkmeyer 2015, Komine 2015). MUTYH Pro516Leu was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. MUTYH Pro516Leu occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available information, it is unclear whether MUTYH Pro516Leu is pathogenic or benign. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH. (less)
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Likely benign
(Jan 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919787.2
First in ClinVar: Jun 02, 2019 Last updated: Feb 12, 2021 |
Comment:
Variant summary: MUTYH c.1547C>T (p.Pro516Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: MUTYH c.1547C>T (p.Pro516Leu) results in a non-conservative amino acid change in 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 2.8e-05 in 251856 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1547C>T has been reported in the literature as a monoallelic variant in at-least one individual affected with APC-mutation negative attenuated familial adenomatous polyposis (AFAP stage III) who reported a negative family history (example, Morak_2010). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. At least two publications reporting experimental evidence evaluating an impact on protein function were ascertained in the context of this evaluation (example, Brinkemeyer_2015, Komine_2015). Both these studies showed no damaging effect of this variant reporting similar DNA binding and glycosylase activity to wild-type enzyme (Brinkemeyer_2015) and a functionally retained ability to compliment the deficiency in an Mut Y disrupted E Coli system by monitoring spontaneous mutation rates (Komine_2015). However, a reduced affinity for PCNA (proliferation cell nuclear antigen), a binding partner of MUTYH protein, was also reported (Brinkmeyer_2015). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign/benign, n=2; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the lack of unequivocal clinical evidence and supportive functional evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Sep 20, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002532253.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020
Comment:
The MUTYH c.1547C>T (p.P516L) variant has been reported in heterozygosity in at least one individual with attenuated familial adenomatous polyposis and at least one individual … (more)
The MUTYH c.1547C>T (p.P516L) variant has been reported in heterozygosity in at least one individual with attenuated familial adenomatous polyposis and at least one individual with breast cancer as well as in unaffected controls (PMID: 33471991, 20618354, 14991577, 14579148). It is also known as c.1505C>T (p.P502L) in the literature. In silico tools suggest the impact of the variant on protein function is benign and in vitro studies indicate that this variant does not affect MUTYH nuclear distribution, DNA binding properties, the amount of active protein, or glycosylase activity (PMID: 26377631, 25820570). However other studies have shown that this variant results in reduced affinity for PCNA, a binding partner of MUTYH protein (PMID: 26377631). This variant was observed in 1/21646 chromosomes in the Finnish population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 134867). The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Jul 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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MYH-associated polyposis
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV000837742.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
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Benign
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 2
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004830916.1
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)
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Number of individuals with the variant: 3
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Likely benign
(May 02, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000186516.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000085799.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
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Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 |
Distinct functional consequences of MUTYH variants associated with colorectal cancer: Damaged DNA affinity, glycosylase activity and interaction with PCNA and Hus1. | Brinkmeyer MK | DNA repair | 2015 | PMID: 26377631 |
Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain. | Komine K | Human mutation | 2015 | PMID: 25820570 |
MUTYH-associated polyposis - variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. | Morak M | Clinical genetics | 2010 | PMID: 20618354 |
Comprehensive analysis of the contribution of germline MYH variation to early-onset colorectal cancer. | Fleischmann C | International journal of cancer | 2004 | PMID: 14991577 |
Inherited variants in MYH are unlikely to contribute to the risk of lung carcinoma. | Al-Tassan N | Human genetics | 2004 | PMID: 14579148 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MUTYH | - | - | - | - |
Text-mined citations for rs587778542 ...
HelpRecord last updated May 08, 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.