VCV000186948.16 - ClinVar

NM_001048174.2(MUTYH):c.1504G>C (p.Asp502His)

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.

(6)

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.1504G>C (p.Asp502His)

Variation ID: 186948 Accession: VCV000186948.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.1 1: 45329368 (GRCh38) [ NCBI UCSC ] 1: 45795040 (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	Jan 6, 2017	May 1, 2024	Oct 10, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001048174.2:c.1504G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001041639.1:p.Asp502His	missense
NM_001128425.2:c.1588G>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001121897.1:p.Asp530His	missense
NM_001048171.2:c.1504G>C	NP_001041636.2:p.Asp502His	missense
NM_001048172.2:c.1507G>C	NP_001041637.1:p.Asp503His	missense
NM_001048173.2:c.1504G>C	NP_001041638.1:p.Asp502His	missense
NM_001293190.2:c.1549G>C	NP_001280119.1:p.Asp517His	missense
NM_001293191.2:c.1537G>C	NP_001280120.1:p.Asp513His	missense
NM_001293192.2:c.1228G>C	NP_001280121.1:p.Asp410His	missense
NM_001293195.2:c.1504G>C	NP_001280124.1:p.Asp502His	missense
NM_001293196.2:c.1228G>C	NP_001280125.1:p.Asp410His	missense
NM_001350650.2:c.1159G>C	NP_001337579.1:p.Asp387His	missense
NM_001350651.2:c.1159G>C	NP_001337580.1:p.Asp387His	missense
NM_012222.3:c.1579G>C	NP_036354.1:p.Asp527His	missense
NR_146882.2:n.1912G>C		non-coding transcript variant
NR_146883.2:n.1761G>C		non-coding transcript variant
NC_000001.11:g.45329368C>G
NC_000001.10:g.45795040C>G
NG_008189.1:g.16103G>C
LRG_220:g.16103G>C
LRG_220t1:c.1588G>C	LRG_220p1:p.Asp530His

... more HGVS ... less HGVS

Protein change

D530H, D516H, D387H, D410H, D527H, D502H, D513H, D503H, D517H

Other names

Canonical SPDI

NC_000001.11:45329367:C:G

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.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA013114 dbSNP: rs147923905 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	Sep 6, 2022	RCV000166616.8
Familial adenomatous polyposis 2	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Oct 10, 2022	RCV000411946.11
not provided	Uncertain significance (1)	criteria provided, single submitter	Jan 27, 2022	RCV002272150.2

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 (Jun 30, 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: SCV001346479.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020
Uncertain significance (Oct 26, 2016)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000487385.2 First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022
Uncertain significance (Oct 10, 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: SCV000545706.8 First in ClinVar: Apr 16, 2017 Last updated: Feb 07, 2023	Comment: This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 530 of the MUTYH protein … (more) This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 530 of the MUTYH protein (p.Asp530His). This variant is present in population databases (rs147923905, gnomAD 0.01%). 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: 186948). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 (Jan 27, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002558527.2 First in ClinVar: Aug 08, 2022 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not … (more) Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 11092888, 23108399) (less)
Uncertain significance (Mar 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004199430.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (Sep 06, 2022)	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: SCV000217420.7 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Comment: The p.D530H variant (also known as c.1588G>C), located in coding exon 16 of the MUTYH gene, results from a G to C substitution at nucleotide … (more) The p.D530H variant (also known as c.1588G>C), located in coding exon 16 of the MUTYH gene, results from a G to C substitution at nucleotide position 1588. The aspartic acid at codon 530 is replaced by histidine, an amino acid with similar properties. This amino acid position is well 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:

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 530 of the MUTYH protein (p.Asp530His). This variant is present in population databases (rs147923905, gnomAD 0.01%). 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: 186948). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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:

Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 11092888, 23108399)

Comment:

The p.D530H variant (also known as c.1588G>C), located in coding exon 16 of the MUTYH gene, results from a G to C substitution at nucleotide position 1588. The aspartic acid at codon 530 is replaced by histidine, an amino acid with similar properties. This amino acid position is well 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

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 rs147923905 ...

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.1504G>C (p.Asp502His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs147923905 ...