VCV000492027.17 - ClinVar

NM_001048174.2(MUTYH):c.1534G>A (p.Asp512Asn)

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.1534G>A (p.Asp512Asn)

Variation ID: 492027 Accession: VCV000492027.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.1 1: 45329338 (GRCh38) [ NCBI UCSC ] 1: 45795010 (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	Dec 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001048174.2:c.1534G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001041639.1:p.Asp512Asn	missense
NM_001128425.2:c.1618G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001121897.1:p.Asp540Asn	missense
NM_001048171.2:c.1534G>A	NP_001041636.2:p.Asp512Asn	missense
NM_001048172.2:c.1537G>A	NP_001041637.1:p.Asp513Asn	missense
NM_001048173.2:c.1534G>A	NP_001041638.1:p.Asp512Asn	missense
NM_001293190.2:c.1579G>A	NP_001280119.1:p.Asp527Asn	missense
NM_001293191.2:c.1567G>A	NP_001280120.1:p.Asp523Asn	missense
NM_001293192.2:c.1258G>A	NP_001280121.1:p.Asp420Asn	missense
NM_001293195.2:c.1534G>A	NP_001280124.1:p.Asp512Asn	missense
NM_001293196.2:c.1258G>A	NP_001280125.1:p.Asp420Asn	missense
NM_001350650.2:c.1189G>A	NP_001337579.1:p.Asp397Asn	missense
NM_001350651.2:c.1189G>A	NP_001337580.1:p.Asp397Asn	missense
NM_012222.3:c.1609G>A	NP_036354.1:p.Asp537Asn	missense
NR_146882.2:n.1942G>A		non-coding transcript variant
NR_146883.2:n.1791G>A		non-coding transcript variant
NC_000001.11:g.45329338C>T
NC_000001.10:g.45795010C>T
NG_008189.1:g.16133G>A
LRG_220:g.16133G>A
LRG_220t1:c.1618G>A	LRG_220p1:p.Asp540Asn

... more HGVS ... less HGVS

Protein change

D540N, D397N, D512N, D513N, D537N, D420N, D523N, D527N

Other names

Canonical SPDI

NC_000001.11:45329337: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 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA340131573 dbSNP: rs1439243449 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	Dec 5, 2023	RCV000584294.9
Familial adenomatous polyposis 2	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 24, 2023	RCV001059206.10

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 (May 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004198942.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (Dec 24, 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: SCV001223823.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Comment: This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 540 of the MUTYH protein … (more) This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 540 of the MUTYH protein (p.Asp540Asn). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 492027). 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 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 (Dec 05, 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: SCV000690544.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Comment: This missense variant replaces aspartic acid with asparagine at codon 540 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein … (more) This missense variant replaces aspartic acid with asparagine at codon 540 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 2/251496 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 (Aug 26, 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: SCV001172885.5 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: The p.D540N variant (also known as c.1618G>A), located in coding exon 16 of the MUTYH gene, results from a G to A substitution at nucleotide … (more) The p.D540N variant (also known as c.1618G>A), located in coding exon 16 of the MUTYH gene, results from a G to A substitution at nucleotide position 1618. The aspartic acid at codon 540 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is not well 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)

Comment:

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 540 of the MUTYH protein (p.Asp540Asn). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 492027). 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 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 aspartic acid with asparagine at codon 540 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 2/251496 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.D540N variant (also known as c.1618G>A), located in coding exon 16 of the MUTYH gene, results from a G to A substitution at nucleotide position 1618. The aspartic acid at codon 540 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is not well 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.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs1439243449 ...

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.1534G>A (p.Asp512Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1439243449 ...