VCV001072724.7 - ClinVar

NM_001048174.2(MUTYH):c.914-1G>T

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.

(2)

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

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.914-1G>T

Variation ID: 1072724 Accession: VCV001072724.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.1 1: 45331850 (GRCh38) [ NCBI UCSC ] 1: 45797522 (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	May 10, 2021	Feb 14, 2024	Oct 6, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_001048174.2:c.914-1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001128425.2:c.998-1G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001048171.2:c.914-1G>T		splice acceptor
NM_001048172.2:c.917-1G>T		splice acceptor
NM_001048173.2:c.914-1G>T		splice acceptor
NM_001293190.2:c.959-1G>T		splice acceptor
NM_001293191.2:c.947-1G>T		splice acceptor
NM_001293192.2:c.638-1G>T		splice acceptor
NM_001293195.2:c.914-1G>T		splice acceptor
NM_001293196.2:c.638-1G>T		splice acceptor
NM_001350650.2:c.569-1G>T		splice acceptor
NM_001350651.2:c.569-1G>T		splice acceptor
NM_001407069.1:c.947-1G>T		splice acceptor
NM_001407070.1:c.914-1G>T		splice acceptor
NM_001407071.1:c.917-1G>T		splice acceptor
NM_001407072.1:c.914-1G>T		splice acceptor
NM_001407073.1:c.914-1G>T		splice acceptor
NM_001407075.1:c.830-1G>T		splice acceptor
NM_001407077.1:c.947-1G>T		splice acceptor
NM_001407078.1:c.917-1G>T		splice acceptor
NM_001407079.1:c.875-1G>T		splice acceptor
NM_001407080.1:c.872-1G>T		splice acceptor
NM_001407081.1:c.914-1G>T		splice acceptor
NM_001407082.1:c.569-1G>T		splice acceptor
NM_001407083.1:c.956-1G>T		splice acceptor
NM_001407085.1:c.956-1G>T		splice acceptor
NM_001407086.1:c.917-1G>T		splice acceptor
NM_001407087.1:c.935-1G>T		splice acceptor
NM_001407088.1:c.914-1G>T		splice acceptor
NM_001407089.1:c.914-1G>T		splice acceptor
NM_001407091.1:c.638-1G>T		splice acceptor
NM_012222.3:c.989-1G>T		splice acceptor
NC_000001.11:g.45331850C>A
NC_000001.10:g.45797522C>A
NG_008189.1:g.13621G>T
LRG_220:g.13621G>T
LRG_220t1:c.998-1G>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000001.11:45331849:C: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

dbSNP: rs2149130255 ClinGen: CA340133947 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	2740	2897

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.
Familial adenomatous polyposis 2	Pathogenic (1)	criteria provided, single submitter	Oct 6, 2021	RCV001385504.5
Hereditary cancer-predisposing syndrome	Likely pathogenic (1)	criteria provided, single submitter	Jun 23, 2020	RCV001523926.2

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.
Likely pathogenic (Jun 23, 2020)	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: SCV001733666.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Comment: This variant causes a G to T nucleotide substitution at the -1 position of intron 11 of the MUTYH gene. Splice site prediction tools predict … (more) This variant causes a G to T nucleotide substitution at the -1 position of intron 11 of the MUTYH gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals with MUTYH-associated polyposis or colorectal cancer plus colorectal polyps (PMID: 17949294, 27705013, 27829682). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Pathogenic (Oct 06, 2021)	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: SCV001585382.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 17949294‚ 27829682‚ 16199547‚ 18534194‚ 20663686 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is also known as c.956-1G>T. Disruption of this splice site has been observed in individual(s) with MUTYH-associated polyposis (PMID: 17949294, 27829682). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 11 of the MUTYH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). (less)

Comment:

This variant causes a G to T nucleotide substitution at the -1 position of intron 11 of the MUTYH gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals with MUTYH-associated polyposis or colorectal cancer plus colorectal polyps (PMID: 17949294, 27705013, 27829682). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is also known as c.956-1G>T. Disruption of this splice site has been observed in individual(s) with MUTYH-associated polyposis (PMID: 17949294, 27829682). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 11 of the MUTYH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686).

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
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
MUTYH-associated polyposis (MAP).	Nielsen M	Critical reviews in oncology/hematology	2011	PMID: 20663686
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
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for rs2149130255 ...

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 Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_001048174.2(MUTYH):c.914-1G>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2149130255 ...