In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Arg231His; This variant is associated with the following publications: (PMID: 16134147, 16287072, 23108399, 24569162, 19732775, 24444654, 25980754, 26694661, 16557584, 28087410, 18534194, 25820570, 17949294, 16455870, 17081686, 26446593, 28551381, 27783336, 27870730, 27829682, 28152038, 26556299, 31159747, 30604180, 30564557, 29625052, 31263571, 29406563, 34426522, 31589614, 32338768, 30787465, 11801590)
ClinVar Genomic variation as it relates to human health
NM_001048174.2(MUTYH):c.650G>A (p.Arg217His)
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.
(28)
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.
Pathogenic/Likely pathogenic
28
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.650G>A (p.Arg217His)
Variation ID: 140877 Accession: VCV000140877.62
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p34.1 1: 45332445 (GRCh38) [ NCBI UCSC ] 1: 45798117 (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 Jul 1, 2016 Oct 20, 2024 Mar 25, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001048174.2:c.650G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001041639.1:p.Arg217His missense NM_001128425.2:c.734G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121897.1:p.Arg245His missense NM_001048171.2:c.650G>A NP_001041636.2:p.Arg217His missense NM_001048172.2:c.653G>A NP_001041637.1:p.Arg218His missense NM_001048173.2:c.650G>A NP_001041638.1:p.Arg217His missense NM_001293190.2:c.695G>A NP_001280119.1:p.Arg232His missense NM_001293191.2:c.683G>A NP_001280120.1:p.Arg228His missense NM_001293192.2:c.374G>A NP_001280121.1:p.Arg125His missense NM_001293195.2:c.650G>A NP_001280124.1:p.Arg217His missense NM_001293196.2:c.374G>A NP_001280125.1:p.Arg125His missense NM_001350650.2:c.305G>A NP_001337579.1:p.Arg102His missense NM_001350651.2:c.305G>A NP_001337580.1:p.Arg102His missense NM_012222.3:c.725G>A NP_036354.1:p.Arg242His missense NR_146882.2:n.878G>A non-coding transcript variant NR_146883.2:n.727G>A non-coding transcript variant NC_000001.11:g.45332445C>T NC_000001.10:g.45798117C>T NG_008189.1:g.13026G>A LRG_220:g.13026G>A LRG_220t1:c.734G>A LRG_220p1:p.Arg245His - Protein change
- R245H, R231H, R102H, R125H, R217H, R242H, R218H, R228H, R232H
- Other names
-
p.R245H:CGT>CAT
- Canonical SPDI
- NC_000001.11:45332444:C:T
-
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.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00008
The Genome Aggregation Database (gnomAD) 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00009
Exome Aggregation Consortium (ExAC) 0.00013
- 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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 12, 2024 | RCV000129105.28 | |
| Pathogenic/Likely pathogenic (10) |
criteria provided, multiple submitters, no conflicts
|
Mar 25, 2024 | RCV000196778.36 | |
| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2023 | RCV000212706.34 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 18, 2017 | RCV000515198.9 | |
| Likely pathogenic (2) |
criteria provided, single submitter
|
Jan 1, 2019 | RCV001262379.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001353906.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 26, 2021 | RCV003313780.9 | |
|
MUTYH-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Nov 22, 2023 | RCV004532545.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 19, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002532325.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MUTYH c.734G>A (p.R245H) variant, also known as c.692G>A (p.R231H) in the literature, has been reported as homozygous and compound heterozygous in numerous individuals with … (more)
The MUTYH c.734G>A (p.R245H) variant, also known as c.692G>A (p.R231H) in the literature, has been reported as homozygous and compound heterozygous in numerous individuals with colorectal polyposis and colorectal cancer (PMID: 16134147, 19732775, 33130102, 24444654, 29406563, 26446593, 23108399, 24569162, among others). Functional studies have shown that this variant decreases MUTYH expression and causes severely defective glycosylase and DNA binding activity (PMID: 18534194, 23108399, 24569162, 25820570). This variant is a well-established pathogenic variant associated with MUTYH-Associated Polyposis (PMID: 19732775, 33130102, 29406563). This variant was observed in 24/281670 chromosomes, with no homozygotes, across all populations in the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 140877). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
|
|
|
|
Pathogenic
(Jan 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000211405.16
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Arg231His; This variant is associated with the … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Arg231His; This variant is associated with the following publications: (PMID: 16134147, 16287072, 23108399, 24569162, 19732775, 24444654, 25980754, 26694661, 16557584, 28087410, 18534194, 25820570, 17949294, 16455870, 17081686, 26446593, 28551381, 27783336, 27870730, 27829682, 28152038, 26556299, 31159747, 30604180, 30564557, 29625052, 31263571, 29406563, 34426522, 31589614, 32338768, 30787465, 11801590) (less)
|
|
|
Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000253868.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 245 of the MUTYH protein (p.Arg245His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 245 of the MUTYH protein (p.Arg245His). This variant is present in population databases (rs140342925, gnomAD 0.03%). This missense change has been observed in individual(s) with familial adenomatous polyposis and colorectal cancer (PMID: 16134147, 16557584, 19732775, 23108399, 24444654, 26446593). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.692G>A (p.Arg231His). ClinVar contains an entry for this variant (Variation ID: 140877). 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. Experimental studies have shown that this missense change affects MUTYH function (PMID: 17081686, 18534194, 23108399, 24569162, 25820570). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848008.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg245His variant in MUTYH has been reported in 1 homozygous individual, 2 heterozygous individuals, and 10 compound heterozygous individuals with MUTYH-related tumors (Aceto 2005, … (more)
The p.Arg245His variant in MUTYH has been reported in 1 homozygous individual, 2 heterozygous individuals, and 10 compound heterozygous individuals with MUTYH-related tumors (Aceto 2005, Olschwang 2007, Russell 2006, Vogt 2009, Win 2014, Yurgelun 2015). It segregated with disease in 3 affected relatives from 2 families (Vogt 2009). It has also been identified in 0.03% (5/19802) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the carrier frequency of MUTYH-related attenuated familial adenomatous polyposis (FAP) in the general population. This variant has been reported in ClinVar (Variation ID: 140877). Functional studies provide some evidence that the p.Arg245His variant has impaired function in vitro (Ali 2008, Ruggieri 2013, Grasso 2014, Komine 2015). In summary, this variant meets criteria to be classified as pathogenic for MUTYH-related attenuated FAP in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PS3_Moderate. (less)
|
|
|
Pathogenic
(Oct 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000183816.10
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.R245H pathogenic mutation (also known as c.734G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at … (more)
The p.R245H pathogenic mutation (also known as c.734G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 734. The arginine at codon 245 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in both the homozygous and compound heterozygous state in multiple individuals with colon polyposis and/or colorectal cancer (Aceto G et al. Hum. Mut. 2005 Oct;26:394; Russell AM et al. Int. J. Cancer. 2006 Apr;118:1937-40; Piccioli P et al. Clin. Chem. 2006 Apr;52:739-43; Olschwang S et al. Genet. Test. 2007;11:315-20; Jones N et al. Gastroenterology. 2009 Aug;137:489-94, 494.e1; quiz 725-6; Vogt S et al. Gastroenterology. 2009 Dec;137:1975-85; Morak M et al. Clin Genet, 2010 Oct;78:353-63; Win AK et al. Gastroenterology. 2014 May;146:1208-11.e1-5; Papp J et al. Fam. Cancer. 2016 Jan;15:85-97; Kacerovska D et al. Am. J. Dermatopathol. 2016 Dec;38:915-92; Ricci MT et al. J Hum Genet, 2017 Feb;62:309-315; Viel A et al. EBioMedicine, 2017 Jun;20:39-49; Yanus GA et al. Clin. Genet. 2018 May;93:1015-1021; Sutcliffe EG et al. Fam Cancer, 2019 04;18:203-209; Staninova-Stojovska M et al. Balkan J Med Genet, 2019 Dec;22:5-16). Functional studies have shown that the p.R245H mutation, which exists in the highly conserved and catalytic domain of MUTYH, results in severely defective glycosylase activity, severely defective DNA binding activity, and protein expression levels roughly half of that compared to wild-type (Ali M et al. Gastroenterology. 2008 Aug;135:499–507; Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). Of note, this alteration is also designated as p.R231H (c.692G>A) in published literature. Based on the available evidence to date, this alteration is classified as a pathogenic mutation. (less)
|
|
|
Pathogenic
(Mar 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004198928.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(May 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002544276.16
First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024 |
Comment:
MUTYH: PS3:Very Strong, PS4, PP3
Number of individuals with the variant: 1
|
|
|
Pathogenic
(May 18, 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: SCV000611287.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
|
|
|
Pathogenic
(Sep 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
MUTYH-associated polyposis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919794.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The MUTYH c.734G>A (p.Arg245His) variant causes a missense change involving the alteration of a conserved nucleotide located in the DNA glycosylase domain and … (more)
Variant summary: The MUTYH c.734G>A (p.Arg245His) variant causes a missense change involving the alteration of a conserved nucleotide located in the DNA glycosylase domain and the Helix-turn-helix, base-excision DNA repair, C-terminal domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional assays showed the variant to be associated with defective glycosylase and DNA binding activity and concluded that this variant is functionally defective (Ali_2008, Komine_2015).The variant was found in the control population dataset of ExAC in 16/119648 control chromosomes at a frequency of 0.0001337, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). This variant has been reported in numerous MUTYH-associated polyposis patients, in both homozygotes and compound heterozygotes (Aceto_2005, Vogt_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Jan 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000821746.2
First in ClinVar: Oct 10, 2018 Last updated: Apr 24, 2020 |
Comment:
This variant is a missense mutation replacing Arginine with Histidine in the position 245 of the MUTYH protein. This particular Arginine is highly conserved and … (more)
This variant is a missense mutation replacing Arginine with Histidine in the position 245 of the MUTYH protein. This particular Arginine is highly conserved and located in a functional domain of the protein (FeS cluster domain). However there is no significant physicochemical difference between Arginine and Histidine (Grantham Score 29). The aforementioned variant has been described in literature both in homozygosity and heterozygosity in patients with MUTYH-associated polyposis (PMID: 17949294 , PMID: 16287072, PMID: 16134147). Furthermore published functional studies have shown that the variant affects MUTYH protein functionality (PMID: 18534194, PMID: 23108399).This mutation is present at low frequency in population databases (rs140342925, 0.01%). The mutation database ClinVar contains an entry for this variant (Variation ID: 140877). (less)
|
|
|
Likely pathogenic
(Jan 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Breast carcinoma
Affected status: no
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440223.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
|
|
|
Pathogenic
(Mar 09, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449871.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(May 27, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368153.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP3.
|
|
|
Pathogenic
(Apr 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: yes
Allele origin:
germline
|
Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499744.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
|
|
|
Likely pathogenic
(Mar 31, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000487344.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
|
|
|
Likely pathogenic
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002011054.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
|
Pathogenic
(Feb 26, 2021)
|
criteria provided, single submitter
Method: research
|
Diffuse midline glioma, H3 K27-altered
Affected status: yes
Allele origin:
germline
|
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital
Accession: SCV004012921.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
|
|
|
Likely pathogenic
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004025001.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
|
|
|
Pathogenic
(Nov 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601660.3
First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024 |
Comment:
The variant has been reported as homozygous or compound heterozygous in multiple individuals with MAP in the published literature (PMID: 23108399 (2013), 19732775 (2009), 16557584 … (more)
The variant has been reported as homozygous or compound heterozygous in multiple individuals with MAP in the published literature (PMID: 23108399 (2013), 19732775 (2009), 16557584 (2006), 16134147 (2005)). Experimental studies indicate the variant is damaging to MUTYH protein function (PMID: 24569162 (2014), 23108399 (2013), 18534194 (2008)). Based on the available information, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Apr 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017633.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Mar 20, 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: SCV000537663.5
First in ClinVar: Sep 24, 2016 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 245 of the MUTYH protein. This variant is also known by an alternative transcript, NM_001048171, as … (more)
This missense variant replaces arginine with histidine at codon 245 of the MUTYH protein. This variant is also known by an alternative transcript, NM_001048171, as c.692G>A (p.Arg231His). A different variant affecting the same codon, c.733C>T (p.Arg245Cys), is considered to be disease-causing (ClinVar variation ID: 41761). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies found this variant to be defective in glycosylase assays (PMID: 18534194, 23108399) and caused abnormal increase in DNA 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and mutation frequency (PMID: 23108399, 24569162). This variant has been reported in multiple individuals who are heterozygous and homozygous carriers and affected with polyposis and colorectal cancer (PMID: 16134147,19394335, 19732775, 23108399, 25590978, 29406563, 29967336, 34704405). This variant has been identified in 24/281670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 08, 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: SCV004839195.1
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 histidine at codon 245 of the MUTYH protein. This variant is also known by an alternative transcript, NM_001048171, as … (more)
This missense variant replaces arginine with histidine at codon 245 of the MUTYH protein. This variant is also known by an alternative transcript, NM_001048171, as c.692G>A (p.Arg231His). A different variant affecting the same codon, c.733C>T (p.Arg245Cys), is considered to be disease-causing (ClinVar variation ID: 41761). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies found this variant to be defective in glycosylase assays (PMID: 18534194, 23108399) and caused abnormal increase in DNA 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and mutation frequency (PMID: 23108399, 24569162). This variant has been reported in multiple individuals who are heterozygous and homozygous carriers and affected with polyposis and colorectal cancer (PMID: 16134147,19394335, 19732775, 23108399, 25590978, 29406563, 29967336, 34704405). This variant has been identified in 24/281670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 20
|
|
|
Pathogenic
(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: SCV005045450.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
|
|
|
Pathogenic
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199297.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Likely pathogenic
(Aug 21, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Breast carcinoma
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Accession: SCV001805831.1
First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
Comment:
Invasive Breast Carcinoma EST= + PRO = - HER2 = - KI = 60-70%
Sex: female
|
|
|
Pathogenic
(Nov 22, 2023)
|
no assertion criteria provided
Method: clinical testing
|
MUTYH-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004116023.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The MUTYH c.734G>A variant is predicted to result in the amino acid substitution p.Arg245His. This variant has been reported in the homozygous and compound heterozygous … (more)
The MUTYH c.734G>A variant is predicted to result in the amino acid substitution p.Arg245His. This variant has been reported in the homozygous and compound heterozygous state in multiple patients to be causative for autosomal recessive adenomatous polyposis coli (sometimes reported as c.692G>A; p.Arg231His in Aceto et al. 2005. PubMed ID: 16134147; Kacerovska et al. 2016. PubMed ID: 27870730; Vogt et al. 2009. PubMed ID: 19732775). Functional studies of the p.Arg245His variant demonstrate that it is deficient in enzymatic and DNA binding activities (Ali et al. 2008. PubMed ID: 18534194), and that it is associated with a statistically significant increase in spontaneous mutation frequency in both homozygous and monoallelic heterozygous lymphoblastoid cell lines derived from MUTYH-associated polyposis patients (Grasso et al. 2014. PubMed ID: 24569162). This variant is reported in 0.025% of alleles in individuals of East Asian descent in gnomAD and has been interpreted as likely pathogenic and pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/140877/). This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Carcinoma of colon
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000592696.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Comment:
The MUTYH p.Arg245His variant was identified in 15 (2 homozygous, remainder were compound heterozygous) of 3360 proband chromosomes (frequency: 0.004) from individuals or families with … (more)
The MUTYH p.Arg245His variant was identified in 15 (2 homozygous, remainder were compound heterozygous) of 3360 proband chromosomes (frequency: 0.004) from individuals or families with MUTYH-associated adenomatous polyposis, familial adenomatous polyposis, or Lynch syndrome and was present in 1 of 2440 control chromosomes (frequency: 0.0004) from healthy individuals (Ruggieri 2013, Vogt 2009, Aceto 2005, Russell 2006, Yanus 2018, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs140342925) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and three other submitters; and classified as likely pathogenic by three submitters), COGR, and UMD-LSDB (23x as causal variant; co-occurring with multiple pathogenic MUTYH mutations). The variant was not identified in Cosmic or MutDB. The variant was identified in control databases in 22 of 276400 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: East Asian in 5 of 18840 chromosomes (freq: 0.0003), Other in 1 of 6454 chromosomes (freq: 0.0002), European in 15 of 126098 chromosomes (freq: 0.0001), and African in 1 of 23930 chromosomes (freq: 0.00004), while the variant was not observed in the Ashkenazi Jewish, Finnish, Latino, or South Asian populations. The p.Arg245 residue is conserved across mammals and other organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. Multiple studies have demonstrated that the p.Arg245His variant has functionally reduced or abolished DNA binding and glycosylase activity (Ali 2008, Komine 2015, Ruggieri 2013, Grasso 2014). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Familial adenomatous polyposis 2
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228643.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Pathogenic and reported on 11-25-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 11-25-2019 by Lab 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:
Myopia (present) , Abnormal retinal morphology (present) , Tinnitus (present)
Indication for testing: Diagnostic
Age: 60-69 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-11-25
Testing laboratory interpretation: Pathogenic
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 245 of the MUTYH protein (p.Arg245His). This variant is present in population databases (rs140342925, gnomAD 0.03%). This missense change has been observed in individual(s) with familial adenomatous polyposis and colorectal cancer (PMID: 16134147, 16557584, 19732775, 23108399, 24444654, 26446593). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.692G>A (p.Arg231His). ClinVar contains an entry for this variant (Variation ID: 140877). 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. Experimental studies have shown that this missense change affects MUTYH function (PMID: 17081686, 18534194, 23108399, 24569162, 25820570). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Arg245His variant in MUTYH has been reported in 1 homozygous individual, 2 heterozygous individuals, and 10 compound heterozygous individuals with MUTYH-related tumors (Aceto 2005, Olschwang 2007, Russell 2006, Vogt 2009, Win 2014, Yurgelun 2015). It segregated with disease in 3 affected relatives from 2 families (Vogt 2009). It has also been identified in 0.03% (5/19802) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the carrier frequency of MUTYH-related attenuated familial adenomatous polyposis (FAP) in the general population. This variant has been reported in ClinVar (Variation ID: 140877). Functional studies provide some evidence that the p.Arg245His variant has impaired function in vitro (Ali 2008, Ruggieri 2013, Grasso 2014, Komine 2015). In summary, this variant meets criteria to be classified as pathogenic for MUTYH-related attenuated FAP in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PS3_Moderate.
Comment:
The p.R245H pathogenic mutation (also known as c.734G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 734. The arginine at codon 245 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in both the homozygous and compound heterozygous state in multiple individuals with colon polyposis and/or colorectal cancer (Aceto G et al. Hum. Mut. 2005 Oct;26:394; Russell AM et al. Int. J. Cancer. 2006 Apr;118:1937-40; Piccioli P et al. Clin. Chem. 2006 Apr;52:739-43; Olschwang S et al. Genet. Test. 2007;11:315-20; Jones N et al. Gastroenterology. 2009 Aug;137:489-94, 494.e1; quiz 725-6; Vogt S et al. Gastroenterology. 2009 Dec;137:1975-85; Morak M et al. Clin Genet, 2010 Oct;78:353-63; Win AK et al. Gastroenterology. 2014 May;146:1208-11.e1-5; Papp J et al. Fam. Cancer. 2016 Jan;15:85-97; Kacerovska D et al. Am. J. Dermatopathol. 2016 Dec;38:915-92; Ricci MT et al. J Hum Genet, 2017 Feb;62:309-315; Viel A et al. EBioMedicine, 2017 Jun;20:39-49; Yanus GA et al. Clin. Genet. 2018 May;93:1015-1021; Sutcliffe EG et al. Fam Cancer, 2019 04;18:203-209; Staninova-Stojovska M et al. Balkan J Med Genet, 2019 Dec;22:5-16). Functional studies have shown that the p.R245H mutation, which exists in the highly conserved and catalytic domain of MUTYH, results in severely defective glycosylase activity, severely defective DNA binding activity, and protein expression levels roughly half of that compared to wild-type (Ali M et al. Gastroenterology. 2008 Aug;135:499–507; Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). Of note, this alteration is also designated as p.R231H (c.692G>A) in published literature. Based on the available evidence to date, this alteration is classified as a pathogenic mutation.
Comment:
MUTYH: PS3:Very Strong, PS4, PP3
Comment:
Variant summary: The MUTYH c.734G>A (p.Arg245His) variant causes a missense change involving the alteration of a conserved nucleotide located in the DNA glycosylase domain and the Helix-turn-helix, base-excision DNA repair, C-terminal domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional assays showed the variant to be associated with defective glycosylase and DNA binding activity and concluded that this variant is functionally defective (Ali_2008, Komine_2015).The variant was found in the control population dataset of ExAC in 16/119648 control chromosomes at a frequency of 0.0001337, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). This variant has been reported in numerous MUTYH-associated polyposis patients, in both homozygotes and compound heterozygotes (Aceto_2005, Vogt_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This variant is a missense mutation replacing Arginine with Histidine in the position 245 of the MUTYH protein. This particular Arginine is highly conserved and located in a functional domain of the protein (FeS cluster domain). However there is no significant physicochemical difference between Arginine and Histidine (Grantham Score 29). The aforementioned variant has been described in literature both in homozygosity and heterozygosity in patients with MUTYH-associated polyposis (PMID: 17949294 , PMID: 16287072, PMID: 16134147). Furthermore published functional studies have shown that the variant affects MUTYH protein functionality (PMID: 18534194, PMID: 23108399).This mutation is present at low frequency in population databases (rs140342925, 0.01%). The mutation database ClinVar contains an entry for this variant (Variation ID: 140877).
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP3.
Comment:
The variant has been reported as homozygous or compound heterozygous in multiple individuals with MAP in the published literature (PMID: 23108399 (2013), 19732775 (2009), 16557584 (2006), 16134147 (2005)). Experimental studies indicate the variant is damaging to MUTYH protein function (PMID: 24569162 (2014), 23108399 (2013), 18534194 (2008)). Based on the available information, this variant is classified as pathogenic.
Comment:
This missense variant replaces arginine with histidine at codon 245 of the MUTYH protein. This variant is also known by an alternative transcript, NM_001048171, as c.692G>A (p.Arg231His). A different variant affecting the same codon, c.733C>T (p.Arg245Cys), is considered to be disease-causing (ClinVar variation ID: 41761). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies found this variant to be defective in glycosylase assays (PMID: 18534194, 23108399) and caused abnormal increase in DNA 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and mutation frequency (PMID: 23108399, 24569162). This variant has been reported in multiple individuals who are heterozygous and homozygous carriers and affected with polyposis and colorectal cancer (PMID: 16134147,19394335, 19732775, 23108399, 25590978, 29406563, 29967336, 34704405). This variant has been identified in 24/281670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This missense variant replaces arginine with histidine at codon 245 of the MUTYH protein. This variant is also known by an alternative transcript, NM_001048171, as c.692G>A (p.Arg231His). A different variant affecting the same codon, c.733C>T (p.Arg245Cys), is considered to be disease-causing (ClinVar variation ID: 41761). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies found this variant to be defective in glycosylase assays (PMID: 18534194, 23108399) and caused abnormal increase in DNA 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and mutation frequency (PMID: 23108399, 24569162). This variant has been reported in multiple individuals who are heterozygous and homozygous carriers and affected with polyposis and colorectal cancer (PMID: 16134147,19394335, 19732775, 23108399, 25590978, 29406563, 29967336, 34704405). This variant has been identified in 24/281670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
Invasive Breast Carcinoma EST= + PRO = - HER2 = - KI = 60-70%
Comment:
The MUTYH c.734G>A variant is predicted to result in the amino acid substitution p.Arg245His. This variant has been reported in the homozygous and compound heterozygous state in multiple patients to be causative for autosomal recessive adenomatous polyposis coli (sometimes reported as c.692G>A; p.Arg231His in Aceto et al. 2005. PubMed ID: 16134147; Kacerovska et al. 2016. PubMed ID: 27870730; Vogt et al. 2009. PubMed ID: 19732775). Functional studies of the p.Arg245His variant demonstrate that it is deficient in enzymatic and DNA binding activities (Ali et al. 2008. PubMed ID: 18534194), and that it is associated with a statistically significant increase in spontaneous mutation frequency in both homozygous and monoallelic heterozygous lymphoblastoid cell lines derived from MUTYH-associated polyposis patients (Grasso et al. 2014. PubMed ID: 24569162). This variant is reported in 0.025% of alleles in individuals of East Asian descent in gnomAD and has been interpreted as likely pathogenic and pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/140877/). This variant is interpreted as pathogenic.
Comment:
The MUTYH p.Arg245His variant was identified in 15 (2 homozygous, remainder were compound heterozygous) of 3360 proband chromosomes (frequency: 0.004) from individuals or families with MUTYH-associated adenomatous polyposis, familial adenomatous polyposis, or Lynch syndrome and was present in 1 of 2440 control chromosomes (frequency: 0.0004) from healthy individuals (Ruggieri 2013, Vogt 2009, Aceto 2005, Russell 2006, Yanus 2018, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs140342925) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and three other submitters; and classified as likely pathogenic by three submitters), COGR, and UMD-LSDB (23x as causal variant; co-occurring with multiple pathogenic MUTYH mutations). The variant was not identified in Cosmic or MutDB. The variant was identified in control databases in 22 of 276400 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: East Asian in 5 of 18840 chromosomes (freq: 0.0003), Other in 1 of 6454 chromosomes (freq: 0.0002), European in 15 of 126098 chromosomes (freq: 0.0001), and African in 1 of 23930 chromosomes (freq: 0.00004), while the variant was not observed in the Ashkenazi Jewish, Finnish, Latino, or South Asian populations. The p.Arg245 residue is conserved across mammals and other organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. Multiple studies have demonstrated that the p.Arg245His variant has functionally reduced or abolished DNA binding and glycosylase activity (Ali 2008, Komine 2015, Ruggieri 2013, Grasso 2014). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
Variant interpreted as Pathogenic and reported on 11-25-2019 by Lab 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:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Arg231His; This variant is associated with the following publications: (PMID: 16134147, 16287072, 23108399, 24569162, 19732775, 24444654, 25980754, 26694661, 16557584, 28087410, 18534194, 25820570, 17949294, 16455870, 17081686, 26446593, 28551381, 27783336, 27870730, 27829682, 28152038, 26556299, 31159747, 30604180, 30564557, 29625052, 31263571, 29406563, 34426522, 31589614, 32338768, 30787465, 11801590)
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 245 of the MUTYH protein (p.Arg245His). This variant is present in population databases (rs140342925, gnomAD 0.03%). This missense change has been observed in individual(s) with familial adenomatous polyposis and colorectal cancer (PMID: 16134147, 16557584, 19732775, 23108399, 24444654, 26446593). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.692G>A (p.Arg231His). ClinVar contains an entry for this variant (Variation ID: 140877). 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. Experimental studies have shown that this missense change affects MUTYH function (PMID: 17081686, 18534194, 23108399, 24569162, 25820570). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Arg245His variant in MUTYH has been reported in 1 homozygous individual, 2 heterozygous individuals, and 10 compound heterozygous individuals with MUTYH-related tumors (Aceto 2005, Olschwang 2007, Russell 2006, Vogt 2009, Win 2014, Yurgelun 2015). It segregated with disease in 3 affected relatives from 2 families (Vogt 2009). It has also been identified in 0.03% (5/19802) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the carrier frequency of MUTYH-related attenuated familial adenomatous polyposis (FAP) in the general population. This variant has been reported in ClinVar (Variation ID: 140877). Functional studies provide some evidence that the p.Arg245His variant has impaired function in vitro (Ali 2008, Ruggieri 2013, Grasso 2014, Komine 2015). In summary, this variant meets criteria to be classified as pathogenic for MUTYH-related attenuated FAP in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PS3_Moderate.
Comment:
The p.R245H pathogenic mutation (also known as c.734G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 734. The arginine at codon 245 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in both the homozygous and compound heterozygous state in multiple individuals with colon polyposis and/or colorectal cancer (Aceto G et al. Hum. Mut. 2005 Oct;26:394; Russell AM et al. Int. J. Cancer. 2006 Apr;118:1937-40; Piccioli P et al. Clin. Chem. 2006 Apr;52:739-43; Olschwang S et al. Genet. Test. 2007;11:315-20; Jones N et al. Gastroenterology. 2009 Aug;137:489-94, 494.e1; quiz 725-6; Vogt S et al. Gastroenterology. 2009 Dec;137:1975-85; Morak M et al. Clin Genet, 2010 Oct;78:353-63; Win AK et al. Gastroenterology. 2014 May;146:1208-11.e1-5; Papp J et al. Fam. Cancer. 2016 Jan;15:85-97; Kacerovska D et al. Am. J. Dermatopathol. 2016 Dec;38:915-92; Ricci MT et al. J Hum Genet, 2017 Feb;62:309-315; Viel A et al. EBioMedicine, 2017 Jun;20:39-49; Yanus GA et al. Clin. Genet. 2018 May;93:1015-1021; Sutcliffe EG et al. Fam Cancer, 2019 04;18:203-209; Staninova-Stojovska M et al. Balkan J Med Genet, 2019 Dec;22:5-16). Functional studies have shown that the p.R245H mutation, which exists in the highly conserved and catalytic domain of MUTYH, results in severely defective glycosylase activity, severely defective DNA binding activity, and protein expression levels roughly half of that compared to wild-type (Ali M et al. Gastroenterology. 2008 Aug;135:499–507; Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). Of note, this alteration is also designated as p.R231H (c.692G>A) in published literature. Based on the available evidence to date, this alteration is classified as a pathogenic mutation.
Comment:
MUTYH: PS3:Very Strong, PS4, PP3
Comment:
Variant summary: The MUTYH c.734G>A (p.Arg245His) variant causes a missense change involving the alteration of a conserved nucleotide located in the DNA glycosylase domain and the Helix-turn-helix, base-excision DNA repair, C-terminal domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional assays showed the variant to be associated with defective glycosylase and DNA binding activity and concluded that this variant is functionally defective (Ali_2008, Komine_2015).The variant was found in the control population dataset of ExAC in 16/119648 control chromosomes at a frequency of 0.0001337, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). This variant has been reported in numerous MUTYH-associated polyposis patients, in both homozygotes and compound heterozygotes (Aceto_2005, Vogt_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This variant is a missense mutation replacing Arginine with Histidine in the position 245 of the MUTYH protein. This particular Arginine is highly conserved and located in a functional domain of the protein (FeS cluster domain). However there is no significant physicochemical difference between Arginine and Histidine (Grantham Score 29). The aforementioned variant has been described in literature both in homozygosity and heterozygosity in patients with MUTYH-associated polyposis (PMID: 17949294 , PMID: 16287072, PMID: 16134147). Furthermore published functional studies have shown that the variant affects MUTYH protein functionality (PMID: 18534194, PMID: 23108399).This mutation is present at low frequency in population databases (rs140342925, 0.01%). The mutation database ClinVar contains an entry for this variant (Variation ID: 140877).
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP3.
Comment:
The variant has been reported as homozygous or compound heterozygous in multiple individuals with MAP in the published literature (PMID: 23108399 (2013), 19732775 (2009), 16557584 (2006), 16134147 (2005)). Experimental studies indicate the variant is damaging to MUTYH protein function (PMID: 24569162 (2014), 23108399 (2013), 18534194 (2008)). Based on the available information, this variant is classified as pathogenic.
Comment:
This missense variant replaces arginine with histidine at codon 245 of the MUTYH protein. This variant is also known by an alternative transcript, NM_001048171, as c.692G>A (p.Arg231His). A different variant affecting the same codon, c.733C>T (p.Arg245Cys), is considered to be disease-causing (ClinVar variation ID: 41761). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies found this variant to be defective in glycosylase assays (PMID: 18534194, 23108399) and caused abnormal increase in DNA 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and mutation frequency (PMID: 23108399, 24569162). This variant has been reported in multiple individuals who are heterozygous and homozygous carriers and affected with polyposis and colorectal cancer (PMID: 16134147,19394335, 19732775, 23108399, 25590978, 29406563, 29967336, 34704405). This variant has been identified in 24/281670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This missense variant replaces arginine with histidine at codon 245 of the MUTYH protein. This variant is also known by an alternative transcript, NM_001048171, as c.692G>A (p.Arg231His). A different variant affecting the same codon, c.733C>T (p.Arg245Cys), is considered to be disease-causing (ClinVar variation ID: 41761). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies found this variant to be defective in glycosylase assays (PMID: 18534194, 23108399) and caused abnormal increase in DNA 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and mutation frequency (PMID: 23108399, 24569162). This variant has been reported in multiple individuals who are heterozygous and homozygous carriers and affected with polyposis and colorectal cancer (PMID: 16134147,19394335, 19732775, 23108399, 25590978, 29406563, 29967336, 34704405). This variant has been identified in 24/281670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
Invasive Breast Carcinoma EST= + PRO = - HER2 = - KI = 60-70%
Comment:
The MUTYH c.734G>A variant is predicted to result in the amino acid substitution p.Arg245His. This variant has been reported in the homozygous and compound heterozygous state in multiple patients to be causative for autosomal recessive adenomatous polyposis coli (sometimes reported as c.692G>A; p.Arg231His in Aceto et al. 2005. PubMed ID: 16134147; Kacerovska et al. 2016. PubMed ID: 27870730; Vogt et al. 2009. PubMed ID: 19732775). Functional studies of the p.Arg245His variant demonstrate that it is deficient in enzymatic and DNA binding activities (Ali et al. 2008. PubMed ID: 18534194), and that it is associated with a statistically significant increase in spontaneous mutation frequency in both homozygous and monoallelic heterozygous lymphoblastoid cell lines derived from MUTYH-associated polyposis patients (Grasso et al. 2014. PubMed ID: 24569162). This variant is reported in 0.025% of alleles in individuals of East Asian descent in gnomAD and has been interpreted as likely pathogenic and pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/140877/). This variant is interpreted as pathogenic.
Comment:
The MUTYH p.Arg245His variant was identified in 15 (2 homozygous, remainder were compound heterozygous) of 3360 proband chromosomes (frequency: 0.004) from individuals or families with MUTYH-associated adenomatous polyposis, familial adenomatous polyposis, or Lynch syndrome and was present in 1 of 2440 control chromosomes (frequency: 0.0004) from healthy individuals (Ruggieri 2013, Vogt 2009, Aceto 2005, Russell 2006, Yanus 2018, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs140342925) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and three other submitters; and classified as likely pathogenic by three submitters), COGR, and UMD-LSDB (23x as causal variant; co-occurring with multiple pathogenic MUTYH mutations). The variant was not identified in Cosmic or MutDB. The variant was identified in control databases in 22 of 276400 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: East Asian in 5 of 18840 chromosomes (freq: 0.0003), Other in 1 of 6454 chromosomes (freq: 0.0002), European in 15 of 126098 chromosomes (freq: 0.0001), and African in 1 of 23930 chromosomes (freq: 0.00004), while the variant was not observed in the Ashkenazi Jewish, Finnish, Latino, or South Asian populations. The p.Arg245 residue is conserved across mammals and other organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. Multiple studies have demonstrated that the p.Arg245His variant has functionally reduced or abolished DNA binding and glycosylase activity (Ali 2008, Komine 2015, Ruggieri 2013, Grasso 2014). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
Variant interpreted as Pathogenic and reported on 11-25-2019 by Lab 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 |
|---|---|---|---|---|
| Filling the gap: A thorough investigation for the genetic diagnosis of unsolved polyposis patients with monoallelic MUTYH pathogenic variants. | Dell'Elice A | Molecular genetics & genomic medicine | 2021 | PMID: 34704405 |
| The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
| Duodenal Adenomas and Cancer in MUTYH-associated Polyposis: An International Cohort Study. | Collaborative Group on Duodenal Polyposis in MAP | Gastroenterology | 2021 | PMID: 33130102 |
| Rare germline genetic variants and risk of aggressive prostate cancer. | Nguyen-Dumont T | International journal of cancer | 2020 | PMID: 32338768 |
| Molecular Basis of Inherited Colorectal Carcinomas in the Macedonian Population: An Update. | Staninova-Stojovska M | Balkan journal of medical genetics : BJMG | 2019 | PMID: 31942411 |
| Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
| High frequency of pathogenic germline variants within homologous recombination repair in patients with advanced cancer. | Bertelsen B | NPJ genomic medicine | 2019 | PMID: 31263571 |
| Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
| Toward automation of germline variant curation in clinical cancer genetics. | Ravichandran V | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30787465 |
| Multi-gene panel testing confirms phenotypic variability in MUTYH-Associated Polyposis. | Sutcliffe EG | Familial cancer | 2019 | PMID: 30604180 |
| Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy. | Rizzolo P | Frontiers in oncology | 2018 | PMID: 30564557 |
| Optimization of the diagnosis of inherited colorectal cancer using NGS and capture of exonic and intronic sequences of panel genes. | Baert-Desurmont S | European journal of human genetics : EJHG | 2018 | PMID: 29967336 |
| Pathogenic Germline Variants in 10,389 Adult Cancers. | Huang KL | Cell | 2018 | PMID: 29625052 |
| Spectrum of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies. | Yanus GA | Clinical genetics | 2018 | PMID: 29406563 |
| A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer. | Viel A | EBioMedicine | 2017 | PMID: 28551381 |
| Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. | LaDuca H | PloS one | 2017 | PMID: 28152038 |
| Type and frequency of MUTYH variants in Italian patients with suspected MAP: a retrospective multicenter study. | Ricci MT | Journal of human genetics | 2017 | PMID: 27829682 |
| Cutaneous Sebaceous Lesions in a Patient With MUTYH-Associated Polyposis Mimicking Muir-Torre Syndrome. | Kacerovska D | The American Journal of dermatopathology | 2016 | PMID: 27870730 |
| Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. | Schrader KA | JAMA oncology | 2016 | PMID: 26556299 |
| Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary. | Papp J | Familial cancer | 2016 | PMID: 26446593 |
| Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
| Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain. | Komine K | Human mutation | 2015 | PMID: 25820570 |
| Racial variation in frequency and phenotypes of APC and MUTYH mutations in 6,169 individuals undergoing genetic testing. | Inra JA | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25590978 |
| Genetic instability in lymphoblastoid cell lines expressing biallelic and monoallelic variants in the human MUTYH gene. | Grasso F | Human molecular genetics | 2014 | PMID: 24569162 |
| Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer. | Win AK | Gastroenterology | 2014 | PMID: 24444654 |
| Loss of MUTYH function in human cells leads to accumulation of oxidative damage and genetic instability. | Ruggieri V | Oncogene | 2013 | PMID: 23108399 |
| 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 |
| Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. | Vogt S | Gastroenterology | 2009 | PMID: 19732775 |
| Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. | Jones N | Gastroenterology | 2009 | PMID: 19394335 |
| Implication of adenomatous polyposis coli and MUTYH mutations in familial colorectal polyposis. | De Rosa M | Diseases of the colon and rectum | 2009 | PMID: 19279422 |
| Characterization of mutant MUTYH proteins associated with familial colorectal cancer. | Ali M | Gastroenterology | 2008 | PMID: 18534194 |
| Similar colorectal cancer risk in patients with monoallelic and biallelic mutations in the MYH gene identified in a population with adenomatous polyposis. | Olschwang S | Genetic testing | 2007 | PMID: 17949294 |
| Functional characterization of human MutY homolog (hMYH) missense mutation (R231L) that is linked with hMYH-associated polyposis. | Bai H | Cancer letters | 2007 | PMID: 17081686 |
| MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. | Aretz S | International journal of cancer | 2006 | PMID: 16557584 |
| Multiplex tetra-primer amplification refractory mutation system PCR to detect 6 common germline mutations of the MUTYH gene associated with polyposis and colorectal cancer. | Piccioli P | Clinical chemistry | 2006 | PMID: 16455870 |
| Prevalence of MYH germline mutations in Swiss APC mutation-negative polyposis patients. | Russell AM | International journal of cancer | 2006 | PMID: 16287072 |
| Mutations of APC and MYH in unrelated Italian patients with adenomatous polyposis coli. | Aceto G | Human mutation | 2005 | PMID: 16134147 |
| click to load more click to collapse | ||||
Text-mined citations for rs140342925 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 27, 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.