VCV000142583.17 - ClinVar

NM_001048174.2(MUTYH):c.1239G>A (p.Glu413=)

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.

(5)

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.

Conflicting classifications of pathogenicity
Uncertain significance(4); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001048174.2(MUTYH):c.1239G>A (p.Glu413=)

Variation ID: 142583 Accession: VCV000142583.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.1 1: 45331420 (GRCh38) [ NCBI UCSC ] 1: 45797092 (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	Apr 17, 2017	May 1, 2024	Oct 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001048174.2:c.1239G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001041639.1:p.Glu413=	synonymous
NM_001128425.2:c.1323G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001121897.1:p.Glu441=	synonymous
NM_001048171.2:c.1239G>A	NP_001041636.2:p.Glu413=	synonymous
NM_001048172.2:c.1242G>A	NP_001041637.1:p.Glu414=	synonymous
NM_001048173.2:c.1239G>A	NP_001041638.1:p.Glu413=	synonymous
NM_001293190.2:c.1284G>A	NP_001280119.1:p.Glu428=	synonymous
NM_001293191.2:c.1272G>A	NP_001280120.1:p.Glu424=	synonymous
NM_001293192.2:c.963G>A	NP_001280121.1:p.Glu321=	synonymous
NM_001293195.2:c.1239G>A	NP_001280124.1:p.Glu413=	synonymous
NM_001293196.2:c.963G>A	NP_001280125.1:p.Glu321=	synonymous
NM_001350650.2:c.894G>A	NP_001337579.1:p.Glu298=	synonymous
NM_001350651.2:c.894G>A	NP_001337580.1:p.Glu298=	synonymous
NM_012222.3:c.1314G>A	NP_036354.1:p.Glu438=	synonymous
NR_146882.2:n.1467G>A		non-coding transcript variant
NR_146883.2:n.1316G>A		non-coding transcript variant
NC_000001.11:g.45331420C>T
NC_000001.10:g.45797092C>T
NG_008189.1:g.14051G>A
LRG_220:g.14051G>A
LRG_220t1:c.1323G>A	LRG_220p1:p.Glu441=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000001.11:45331419: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

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA012624 dbSNP: rs587782564 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	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jun 23, 2020	RCV000131785.12
not provided	Uncertain significance (1)	criteria provided, single submitter	Oct 2, 2017	RCV000579114.1
Familial adenomatous polyposis 2	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 24, 2023	RCV000462220.8

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 (Oct 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004198802.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (Jan 23, 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: SCV000545729.7 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 17576681‚ 9536098 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 142583). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is present in population databases (rs587782564, gnomAD 0.007%). This sequence change affects codon 441 of the MUTYH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MUTYH protein. This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. (less)
Likely benign (Jun 23, 2020)	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: SCV000186834.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (Oct 02, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000680806.3 First in ClinVar: Feb 13, 2018 Last updated: Feb 13, 2018	Comment: This variant is denoted MUTYH c.1323G>A at the DNA level. This variant is silent at the coding level, preserving a Glutamic Acid at codon 441. … (more) This variant is denoted MUTYH c.1323G>A at the DNA level. This variant is silent at the coding level, preserving a Glutamic Acid at codon 441. It is not predicted to cause abnormal splicing. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). The nucleotide which is altered, a guanine (G) at base 1323, is conserved across species. Based on currently available information, it is unclear whether MUTYH c.1323G>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH. (less)
Uncertain significance (Oct 28, 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: SCV001352097.2 First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022	Comment: This synonymous variant does not change the amino acid sequence of the MUTYH protein. However, splice prediction tools suggest that this variant may disrupt RNA … (more) This synonymous variant does not change the amino acid sequence of the MUTYH protein. However, splice prediction tools suggest that this variant may disrupt RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer 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)

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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 142583). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is present in population databases (rs587782564, gnomAD 0.007%). This sequence change affects codon 441 of the MUTYH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MUTYH protein. This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

This variant is denoted MUTYH c.1323G>A at the DNA level. This variant is silent at the coding level, preserving a Glutamic Acid at codon 441. It is not predicted to cause abnormal splicing. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). The nucleotide which is altered, a guanine (G) at base 1323, is conserved across species. Based on currently available information, it is unclear whether MUTYH c.1323G>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.

Comment:

This synonymous variant does not change the amino acid sequence of the MUTYH protein. However, splice prediction tools suggest that this variant may disrupt RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer 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.

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
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs587782564 ...

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.1239G>A (p.Glu413=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587782564 ...