The p.R191W variant (also known as c.571C>T), located in coding exon 7 of the MUTYH gene, results from a C to T substitution at nucleotide position 571. The arginine at codon 191 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration, designated as p.Arg177Trp, was detected in a Spanish patient diagnosed at age 29 with left-sided colon cancer but with no associated polyps (Riegert-Johnson DL et al. Genet Test, 2007;11:361-5). This alteration was also identified in a cohort of 882 Chinese individuals who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci., 2020 Feb;111:647-657). 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.
ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.487C>T (p.Arg163Trp)
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.
(11)
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
11
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.487C>T (p.Arg163Trp)
Variation ID: 186056 Accession: VCV000186056.30
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p34.1 1: 45332768 (GRCh38) [ NCBI UCSC ] 1: 45798440 (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 Feb 19, 2018 Oct 8, 2024 Jun 12, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001048174.2:c.487C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Arg163Trp missense NM_001128425.2:c.571C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Arg191Trp missense NM_001048171.2:c.487C>T NP_001041636.2:p.Arg163Trp missense NM_001048172.2:c.490C>T NP_001041637.1:p.Arg164Trp missense NM_001048173.2:c.487C>T NP_001041638.1:p.Arg163Trp missense NM_001293190.2:c.532C>T NP_001280119.1:p.Arg178Trp missense NM_001293191.2:c.520C>T NP_001280120.1:p.Arg174Trp missense NM_001293192.2:c.211C>T NP_001280121.1:p.Arg71Trp missense NM_001293195.2:c.487C>T NP_001280124.1:p.Arg163Trp missense NM_001293196.2:c.211C>T NP_001280125.1:p.Arg71Trp missense NM_001350650.2:c.142C>T NP_001337579.1:p.Arg48Trp missense NM_001350651.2:c.142C>T NP_001337580.1:p.Arg48Trp missense NM_012222.3:c.562C>T NP_036354.1:p.Arg188Trp missense NR_146882.2:n.715C>T non-coding transcript variant NR_146883.2:n.564C>T non-coding transcript variant NC_000001.11:g.45332768G>A NC_000001.10:g.45798440G>A NG_008189.1:g.12703C>T LRG_220:g.12703C>T LRG_220t1:c.571C>T LRG_220p1:p.Arg191Trp - Protein change
- R191W, R177W, R164W, R71W, R174W, R163W, R178W, R188W, R48W
- Other names
- -
- Canonical SPDI
- NC_000001.11:45332767: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.
-
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- 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 |
2688 | 2844 | |
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
|
Apr 24, 2023 | RCV000165580.15 | |
| Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
|
Feb 5, 2024 | RCV000204489.17 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jun 12, 2024 | RCV001594862.6 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Nov 27, 2023 | RCV003479037.1 |
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
(Sep 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004198871.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Uncertain significance
(Nov 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000216314.9
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.R191W variant (also known as c.571C>T), located in coding exon 7 of the MUTYH gene, results from a C to T substitution at nucleotide … (more)
The p.R191W variant (also known as c.571C>T), located in coding exon 7 of the MUTYH gene, results from a C to T substitution at nucleotide position 571. The arginine at codon 191 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration, designated as p.Arg177Trp, was detected in a Spanish patient diagnosed at age 29 with left-sided colon cancer but with no associated polyps (Riegert-Johnson DL et al. Genet Test, 2007;11:361-5). This alteration was also identified in a cohort of 882 Chinese individuals who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci., 2020 Feb;111:647-657). 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. (less)
|
|
|
Uncertain significance
(Nov 27, 2023)
|
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: SCV004223177.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: MUTYH c.571C>T (p.Arg191Trp) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Four of … (more)
Variant summary: MUTYH c.571C>T (p.Arg191Trp) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251480 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.571C>T has been reported in the literature in heterozygous individuals affected with colorectal cancer without associated polyps, cardiac dysfunction, and increased risk of hereditary breast and ovarian cancer (e.g. Riegert-Johnson_2007, Lam_2015, Shao_2020). 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: 28491533, 18294051, 31742824). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
|
Uncertain significance
(Apr 24, 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: SCV000685644.6
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with tryptophan at codon 191 of the MUTYH protein. This variant is also known as NM_001048171.1:c.529C>T (p.Arg177Trp) in the literature. … (more)
This missense variant replaces arginine with tryptophan at codon 191 of the MUTYH protein. This variant is also known as NM_001048171.1:c.529C>T (p.Arg177Trp) in the literature. 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: 18294051) or breast cancer (PMID: 31742824, 33471991). In a large international case-control meta-analysis, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 3/251480 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
(Feb 05, 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: SCV004837290.1
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 tryptophan at codon 191 of the MUTYH protein. This variant is also known as NM_001048171.1:c.529C>T (p.Arg177Trp) in the literature. … (more)
This missense variant replaces arginine with tryptophan at codon 191 of the MUTYH protein. This variant is also known as NM_001048171.1:c.529C>T (p.Arg177Trp) in the literature. 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: 18294051) or breast cancer (PMID: 31742824, 33471991). In a large international case-control meta-analysis, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 3/251480 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: 3
|
|
|
Uncertain significance
(Jan 22, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000797302.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
|
|
|
Uncertain significance
(Jun 24, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002532300.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MUTYH c.571C>T (p.R191W) variant has been reported in at least one individual with early onset colorectal cancer and in at least three individuals with … (more)
The MUTYH c.571C>T (p.R191W) variant has been reported in at least one individual with early onset colorectal cancer and in at least three individuals with a personal/family history of breast and/or ovarian cancer (PMID: 18294051, 31742824, 33471991). It was observed in 1/16248 chromosomes of the African/African American subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 186056). In silico tools suggest the impact of the variant on protein function is inconclusive, though these predictions have not been confirmed by functional studies. 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
(Dec 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579583.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM1, PM2_SUP, PP3
|
Number of individuals with the variant: 1
Sex: female
|
|
|
Uncertain significance
(Jan 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000262259.12
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 191 of the MUTYH protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 191 of the MUTYH protein (p.Arg191Trp). This variant is present in population databases (rs761101420, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer and/or personal or family history of hereditary breast and ovarian cancer (PMID: 18294051, 31742824). This variant is also known as p.Arg177Trp. ClinVar contains an entry for this variant (Variation ID: 186056). 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
(Jun 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001829302.4
First in ClinVar: Sep 08, 2021 Last updated: Oct 08, 2024 |
Comment:
Observed in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 31742824); Not observed at significant frequency in large population cohorts (gnomAD); … (more)
Observed in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 31742824); 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; Also known as c.529C>T (p.R177W); This variant is associated with the following publications: (PMID: 18294051, 33471991, 28491533, 31742824) (less)
|
|
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not provided
(-)
|
no classification provided
Method: phenotyping only
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749674.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Uncertain significance and reported on 06-18-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Uncertain significance and reported on 06-18-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Family history of cancer (present)
Indication for testing: Presymptomatic
Age: 40-49 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2018-06-18
Testing laboratory interpretation: Uncertain significance
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Comment:
Comment:
Variant summary: MUTYH c.571C>T (p.Arg191Trp) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251480 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.571C>T has been reported in the literature in heterozygous individuals affected with colorectal cancer without associated polyps, cardiac dysfunction, and increased risk of hereditary breast and ovarian cancer (e.g. Riegert-Johnson_2007, Lam_2015, Shao_2020). 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: 28491533, 18294051, 31742824). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
This missense variant replaces arginine with tryptophan at codon 191 of the MUTYH protein. This variant is also known as NM_001048171.1:c.529C>T (p.Arg177Trp) in the literature. 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: 18294051) or breast cancer (PMID: 31742824, 33471991). In a large international case-control meta-analysis, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 3/251480 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 tryptophan at codon 191 of the MUTYH protein. This variant is also known as NM_001048171.1:c.529C>T (p.Arg177Trp) in the literature. 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: 18294051) or breast cancer (PMID: 31742824, 33471991). In a large international case-control meta-analysis, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 3/251480 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 sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 191 of the MUTYH protein (p.Arg191Trp). This variant is present in population databases (rs761101420, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer and/or personal or family history of hereditary breast and ovarian cancer (PMID: 18294051, 31742824). This variant is also known as p.Arg177Trp. ClinVar contains an entry for this variant (Variation ID: 186056). 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:
Observed in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 31742824); 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; Also known as c.529C>T (p.R177W); This variant is associated with the following publications: (PMID: 18294051, 33471991, 28491533, 31742824)
Comment:
Variant interpreted as Uncertain significance and reported on 06-18-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
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:
The p.R191W variant (also known as c.571C>T), located in coding exon 7 of the MUTYH gene, results from a C to T substitution at nucleotide position 571. The arginine at codon 191 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration, designated as p.Arg177Trp, was detected in a Spanish patient diagnosed at age 29 with left-sided colon cancer but with no associated polyps (Riegert-Johnson DL et al. Genet Test, 2007;11:361-5). This alteration was also identified in a cohort of 882 Chinese individuals who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci., 2020 Feb;111:647-657). 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.
Comment:
Variant summary: MUTYH c.571C>T (p.Arg191Trp) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251480 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.571C>T has been reported in the literature in heterozygous individuals affected with colorectal cancer without associated polyps, cardiac dysfunction, and increased risk of hereditary breast and ovarian cancer (e.g. Riegert-Johnson_2007, Lam_2015, Shao_2020). 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: 28491533, 18294051, 31742824). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
This missense variant replaces arginine with tryptophan at codon 191 of the MUTYH protein. This variant is also known as NM_001048171.1:c.529C>T (p.Arg177Trp) in the literature. 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: 18294051) or breast cancer (PMID: 31742824, 33471991). In a large international case-control meta-analysis, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 3/251480 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 tryptophan at codon 191 of the MUTYH protein. This variant is also known as NM_001048171.1:c.529C>T (p.Arg177Trp) in the literature. 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: 18294051) or breast cancer (PMID: 31742824, 33471991). In a large international case-control meta-analysis, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 3/251480 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 sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 191 of the MUTYH protein (p.Arg191Trp). This variant is present in population databases (rs761101420, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer and/or personal or family history of hereditary breast and ovarian cancer (PMID: 18294051, 31742824). This variant is also known as p.Arg177Trp. ClinVar contains an entry for this variant (Variation ID: 186056). 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:
Observed in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 31742824); 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; Also known as c.529C>T (p.R177W); This variant is associated with the following publications: (PMID: 18294051, 33471991, 28491533, 31742824)
Comment:
Variant interpreted as Uncertain significance and reported on 06-18-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Prevalence of hereditary breast and ovarian cancer (HBOC) predisposition gene mutations among 882 HBOC high-risk Chinese individuals. | Shao D | Cancer science | 2020 | PMID: 31742824 |
| Exome sequencing identifies a novel mutation in the MYH6 gene in a family with early-onset sinus node dysfunction, ventricular arrhythmias, and cardiac arrest. | Lam L | HeartRhythm case reports | 2015 | PMID: 28491533 |
| The value of MUTYH testing in patients with early onset microsatellite stable colorectal cancer referred for hereditary nonpolyposis colon cancer syndrome testing. | Riegert-Johnson DL | Genetic testing | 2007 | PMID: 18294051 |
Text-mined citations for rs761101420 ...
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Record last updated Oct 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.