VCV000186723.21 - ClinVar

NM_001048174.2(MUTYH):c.1321G>A (p.Val441Ile)

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.

(8)

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.1321G>A (p.Val441Ile)

Variation ID: 186723 Accession: VCV000186723.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.1 1: 45796925 (GRCh37) [ NCBI UCSC ] 1: 45331253 (GRCh38) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 29, 2017	Oct 8, 2024	Sep 6, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001048174.2:c.1321G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001041639.1:p.Val441Ile	missense
NM_001128425.2:c.1405G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001121897.1:p.Val469Ile	missense
NM_001048171.2:c.1321G>A	NP_001041636.2:p.Val441Ile	missense
NM_001048172.2:c.1324G>A	NP_001041637.1:p.Val442Ile	missense
NM_001048173.2:c.1321G>A	NP_001041638.1:p.Val441Ile	missense
NM_001293190.2:c.1366G>A	NP_001280119.1:p.Val456Ile	missense
NM_001293191.2:c.1354G>A	NP_001280120.1:p.Val452Ile	missense
NM_001293192.2:c.1045G>A	NP_001280121.1:p.Val349Ile	missense
NM_001293195.2:c.1321G>A	NP_001280124.1:p.Val441Ile	missense
NM_001293196.2:c.1045G>A	NP_001280125.1:p.Val349Ile	missense
NM_001350650.2:c.976G>A	NP_001337579.1:p.Val326Ile	missense
NM_001350651.2:c.976G>A	NP_001337580.1:p.Val326Ile	missense
NM_012222.3:c.1396G>A	NP_036354.1:p.Val466Ile	missense
NR_146882.2:n.1549G>A		non-coding transcript variant
NR_146883.2:n.1398G>A		non-coding transcript variant
NC_000001.11:g.45331253C>T
NC_000001.10:g.45796925C>T
NG_008189.1:g.14218G>A
LRG_220:g.14218G>A
LRG_220t1:c.1405G>A	LRG_220p1:p.Val469Ile

... more HGVS ... less HGVS

Protein change

V469I, V455I, V326I, V442I, V452I, V456I, V349I, V466I, V441I

Other names

Canonical SPDI

NC_000001.11:45331252:C:T

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.

Exome Aggregation Consortium (ExAC) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA012695 dbSNP: rs779701238 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 (3)	criteria provided, multiple submitters, no conflicts	Oct 2, 2023	RCV000166365.13
Familial adenomatous polyposis 2	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000197060.14
not provided	Uncertain significance (1)	criteria provided, single submitter	Sep 6, 2024	RCV000484811.4
MUTYH-related disorder	Uncertain significance (1)	no assertion criteria provided	Mar 23, 2024	RCV004739534.1

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 (Mar 08, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000790221.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018
Uncertain significance (Aug 28, 2023)	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: SCV000685572.5 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Comment: This missense variant replaces valine with isoleucine at codon 469 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces valine with isoleucine at codon 469 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 4/251492 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 (Oct 02, 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: SCV000217154.7 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Comment: The p.V469I variant (also known as c.1405G>A), located in coding exon 14 of the MUTYH gene, results from a G to A substitution at nucleotide … (more) The p.V469I variant (also known as c.1405G>A), located in coding exon 14 of the MUTYH gene, results from a G to A substitution at nucleotide position 1405. The valine at codon 469 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Jun 18, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002532232.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The MUTYH c.1405G>A (p.V469I) variant has been reported in 2/60466 breast cancer cases and 1/53461 healthy controls by a large case-control study (PMID: 33471991). This … (more) The MUTYH c.1405G>A (p.V469I) variant has been reported in 2/60466 breast cancer cases and 1/53461 healthy controls by a large case-control study (PMID: 33471991). This variant was observed in 1/16256 chromosomes in the African population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654) and has been reported in ClinVar (Variation ID: 186723). In silico tools suggest the impact of the variant on protein function is inconclusive, though these predictions have not been confirmed by functional studies. Based on the current evidence available, this variant is interpreted as a variant of uncertain significance. (less)	Publications: PubMed (1) PubMed: 33471991
Uncertain significance (Aug 31, 2022)	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: SCV000254701.11 First in ClinVar: Oct 11, 2015 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 469 of the MUTYH protein (p.Val469Ile). … (more) This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 469 of the MUTYH protein (p.Val469Ile). This variant is present in population databases (rs779701238, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 186723). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 (Aug 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: SCV004828479.1 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 valine with isoleucine at codon 469 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces valine with isoleucine at codon 469 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/251492 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: 2
Uncertain significance (Sep 06, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000567080.7 First in ClinVar: Apr 29, 2017 Last updated: Oct 08, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in cases and controls in a breast cancer case-control study (PMID: 33471991); This variant is associated with the following publications: (PMID: 23108399, 33471991) (less)
Uncertain significance (Mar 23, 2024)	no assertion criteria provided Method: clinical testing	MUTYH-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005351142.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The MUTYH c.1405G>A variant is predicted to result in the amino acid substitution p.Val469Ile. In a large-scale study of breast cancer risk genes, this variant … (more) The MUTYH c.1405G>A variant is predicted to result in the amino acid substitution p.Val469Ile. In a large-scale study of breast cancer risk genes, this variant was identified in two patients with breast cancer and in one control patient (Breast Cancer Association Consortium et al 2021. PubMed ID: 33471991). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. In ClinVar, this variant is interpreted as having uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/186723/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

This missense variant replaces valine with isoleucine at codon 469 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 4/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

The p.V469I variant (also known as c.1405G>A), located in coding exon 14 of the MUTYH gene, results from a G to A substitution at nucleotide position 1405. The valine at codon 469 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 469 of the MUTYH protein (p.Val469Ile). This variant is present in population databases (rs779701238, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 186723). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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:

This missense variant replaces valine with isoleucine at codon 469 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/251492 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:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in cases and controls in a breast cancer case-control study (PMID: 33471991); This variant is associated with the following publications: (PMID: 23108399, 33471991)

Comment:

The MUTYH c.1405G>A variant is predicted to result in the amino acid substitution p.Val469Ile. In a large-scale study of breast cancer risk genes, this variant was identified in two patients with breast cancer and in one control patient (Breast Cancer Association Consortium et al 2021. PubMed ID: 33471991). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. In ClinVar, this variant is interpreted as having uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/186723/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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:

This missense variant replaces valine with isoleucine at codon 469 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/251492 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:

Citations for germline classification of this variant

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

Text-mined citations for rs779701238 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_001048174.2(MUTYH):c.1321G>A (p.Val441Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs779701238 ...