VCV000185604.27 - ClinVar

NM_001048174.2(MUTYH):c.310G>A (p.Val104Ile)

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.

(9)

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.310G>A (p.Val104Ile)

Variation ID: 185604 Accession: VCV000185604.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.1 1: 45333165 (GRCh38) [ NCBI UCSC ] 1: 45798837 (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	Aug 11, 2024	Mar 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001048174.2:c.310G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001041639.1:p.Val104Ile	missense
NM_001128425.2:c.394G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001121897.1:p.Val132Ile	missense
NM_001048171.2:c.310G>A	NP_001041636.2:p.Val104Ile	missense
NM_001048172.2:c.313G>A	NP_001041637.1:p.Val105Ile	missense
NM_001048173.2:c.310G>A	NP_001041638.1:p.Val104Ile	missense
NM_001293190.2:c.355G>A	NP_001280119.1:p.Val119Ile	missense
NM_001293191.2:c.343G>A	NP_001280120.1:p.Val115Ile	missense
NM_001293192.2:c.34G>A	NP_001280121.1:p.Val12Ile	missense
NM_001293195.2:c.310G>A	NP_001280124.1:p.Val104Ile	missense
NM_001293196.2:c.34G>A	NP_001280125.1:p.Val12Ile	missense
NM_001350650.2:c.33+120G>A		intron variant
NM_001350651.2:c.33+120G>A		intron variant
NM_012222.3:c.385G>A	NP_036354.1:p.Val129Ile	missense
NR_146882.2:n.538G>A		non-coding transcript variant
NC_000001.11:g.45333165C>T
NC_000001.10:g.45798837C>T
NG_008189.1:g.12306G>A
LRG_220:g.12306G>A
LRG_220t1:c.394G>A	LRG_220p1:p.Val132Ile

... more HGVS ... less HGVS

Protein change

V132I, V115I, V119I, V104I, V105I, V129I, V12I

Other names

Canonical SPDI

NC_000001.11:45333164: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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA013526 dbSNP: rs763273196 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	2689	2845

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	Mar 24, 2024	RCV000165052.15
Familial adenomatous polyposis 2	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV000466109.16
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 20, 2021	RCV000590403.6
Familial adenomatous polyposis 2 Gastric cancer	Uncertain significance (1)	criteria provided, single submitter	Dec 15, 2021	RCV002478507.2
not specified	Uncertain significance (1)	criteria provided, single submitter	Sep 14, 2021	RCV001731494.2

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.
Uncertain significance (Aug 20, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001871353.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has … (more) Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)
Uncertain significance (Sep 14, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697695.2 First in ClinVar: Mar 17, 2018 Last updated: Oct 30, 2021	Publications: PubMed (2) PubMed: 26689913‚ 30374176 Comment: Variant summary: MUTYH c.394G>A (p.Val132Ile) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Three of … (more) Variant summary: MUTYH c.394G>A (p.Val132Ile) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251414 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.394G>A has been reported in the literature in four individuals affected with different types of cancer in one family (Tsai_2019). These report does not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. Additionally, co-occurrences with another pathogenic variant have been reported (RAD51D exon 7-10 deletion), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Jul 23, 2019)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001134477.2 First in ClinVar: Jan 05, 2020 Last updated: Jan 01, 2022
Uncertain significance (Dec 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Gastric cancer Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002790174.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Dec 20, 2022)	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: SCV000685626.5 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Comment: This missense variant replaces valine with isoleucine at codon 132 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces valine with isoleucine at codon 132 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 1/251414 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 (Jan 25, 2024)	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: SCV000545738.10 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024	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 132 of the MUTYH protein (p.Val132Ile). … (more) This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 132 of the MUTYH protein (p.Val132Ile). This variant is present in population databases (rs763273196, gnomAD 0.0009%). 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: 185604). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain Significance (Feb 05, 2024)	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: SCV004839816.1 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 132 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces valine with isoleucine at codon 132 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 1/251414 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: 4
Uncertain significance (Jan 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004198870.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Mar 24, 2024)	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: SCV000215753.9 First in ClinVar: Mar 24, 2015 Last updated: Aug 11, 2024	Comment: The p.V132I variant (also known as c.394G>A), located in coding exon 5 of the MUTYH gene, results from a G to A substitution at nucleotide … (more) The p.V132I variant (also known as c.394G>A), located in coding exon 5 of the MUTYH gene, results from a G to A substitution at nucleotide position 394. The valine at codon 132 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Comment:

Variant summary: MUTYH c.394G>A (p.Val132Ile) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251414 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.394G>A has been reported in the literature in four individuals affected with different types of cancer in one family (Tsai_2019). These report does not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. Additionally, co-occurrences with another pathogenic variant have been reported (RAD51D exon 7-10 deletion), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

This missense variant replaces valine with isoleucine at codon 132 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 1/251414 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 132 of the MUTYH protein (p.Val132Ile). This variant is present in population databases (rs763273196, gnomAD 0.0009%). 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: 185604). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The p.V132I variant (also known as c.394G>A), located in coding exon 5 of the MUTYH gene, results from a G to A substitution at nucleotide position 394. The valine at codon 132 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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
Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance.	Tsai GJ	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30374176
Patterns and functional implications of rare germline variants across 12 cancer types.	Lu C	Nature communications	2015	PMID: 26689913

Text-mined citations for rs763273196 ...

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.310G>A (p.Val104Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs763273196 ...