VCV000230300.18 - ClinVar

NM_001048174.2(MUTYH):c.596C>T (p.Ala199Val)

Germline

Classification

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.

(4)

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

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.596C>T (p.Ala199Val)

Variation ID: 230300 Accession: VCV000230300.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.1 1: 45332584 (GRCh38) [ NCBI UCSC ] 1: 45798256 (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	May 1, 2024	Sep 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001048174.2:c.596C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001041639.1:p.Ala199Val	missense
NM_001128425.2:c.680C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001121897.1:p.Ala227Val	missense
NM_001048171.2:c.596C>T	NP_001041636.2:p.Ala199Val	missense
NM_001048172.2:c.599C>T	NP_001041637.1:p.Ala200Val	missense
NM_001048173.2:c.596C>T	NP_001041638.1:p.Ala199Val	missense
NM_001293190.2:c.641C>T	NP_001280119.1:p.Ala214Val	missense
NM_001293191.2:c.629C>T	NP_001280120.1:p.Ala210Val	missense
NM_001293192.2:c.320C>T	NP_001280121.1:p.Ala107Val	missense
NM_001293195.2:c.596C>T	NP_001280124.1:p.Ala199Val	missense
NM_001293196.2:c.320C>T	NP_001280125.1:p.Ala107Val	missense
NM_001350650.2:c.251C>T	NP_001337579.1:p.Ala84Val	missense
NM_001350651.2:c.251C>T	NP_001337580.1:p.Ala84Val	missense
NM_012222.3:c.671C>T	NP_036354.1:p.Ala224Val	missense
NR_146882.2:n.824C>T		non-coding transcript variant
NR_146883.2:n.673C>T		non-coding transcript variant
NC_000001.11:g.45332584G>A
NC_000001.10:g.45798256G>A
NG_008189.1:g.12887C>T
LRG_220:g.12887C>T
LRG_220t1:c.680C>T	LRG_220p1:p.Ala227Val

... more HGVS ... less HGVS

Protein change

A227V, A199V, A107V, A214V, A224V, A84V, A200V, A210V

Other names

Canonical SPDI

NC_000001.11:45332583:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA10577726 dbSNP: rs11545695 VarSome

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
Gene	OMIM	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.
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 24, 2023	RCV000218668.9
Familial adenomatous polyposis 2	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 27, 2023	RCV000475653.14

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 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000545794.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 28492532‚ 25820570‚ 21520333 Comment: 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 … (more) 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MUTYH function (PMID: 25820570). 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. ClinVar contains an entry for this variant (Variation ID: 230300). This missense change has been observed in individual(s) with clinical features of MUTYH-related conditions (PMID: 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 227 of the MUTYH protein (p.Ala227Val). (less)
Uncertain significance (Feb 24, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000273794.8 First in ClinVar: May 29, 2016 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 25820570 Comment: The p.A227V variant (also known as c.680C>T), located in coding exon 8 of the MUTYH gene, results from a C to T substitution at nucleotide … (more) The p.A227V variant (also known as c.680C>T), located in coding exon 8 of the MUTYH gene, results from a C to T substitution at nucleotide position 680. The alanine at codon 227 is replaced by valine, an amino acid with similar properties. In a study assessing the base excision repair capabilities of several MUTYH variants, this alteration was found to be partially defective (Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Feb 21, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000685657.3 First in ClinVar: Feb 19, 2018 Last updated: Jun 22, 2020
Uncertain Significance (May 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV004841537.1 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)	Number of individuals with the variant: 1

Comment:

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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MUTYH function (PMID: 25820570). 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. ClinVar contains an entry for this variant (Variation ID: 230300). This missense change has been observed in individual(s) with clinical features of MUTYH-related conditions (PMID: 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 227 of the MUTYH protein (p.Ala227Val).

Comment:

The p.A227V variant (also known as c.680C>T), located in coding exon 8 of the MUTYH gene, results from a C to T substitution at nucleotide position 680. The alanine at codon 227 is replaced by valine, an amino acid with similar properties. In a study assessing the base excision repair capabilities of several MUTYH variants, this alteration was found to be partially defective (Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain.	Komine K	Human mutation	2015	PMID: 25820570
LOVD v.2.0: the next generation in gene variant databases.	Fokkema IF	Human mutation	2011	PMID: 21520333

Text-mined citations for rs11545695 ...

These 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001048174.2(MUTYH):c.596C>T (p.Ala199Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs11545695 ...