VCV000127846.27 - ClinVar

NM_001048174.2(MUTYH):c.488G>A (p.Arg163Gln)

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.

(12)

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(11); 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.488G>A (p.Arg163Gln)

Variation ID: 127846 Accession: VCV000127846.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.1 1: 45332767 (GRCh38) [ NCBI UCSC ] 1: 45798439 (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	Dec 6, 2016	Sep 16, 2024	Mar 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001048174.2:c.488G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001041639.1:p.Arg163Gln	missense
NM_001128425.2:c.572G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001121897.1:p.Arg191Gln	missense
NM_001048171.2:c.488G>A	NP_001041636.2:p.Arg163Gln	missense
NM_001048172.2:c.491G>A	NP_001041637.1:p.Arg164Gln	missense
NM_001048173.2:c.488G>A	NP_001041638.1:p.Arg163Gln	missense
NM_001293190.2:c.533G>A	NP_001280119.1:p.Arg178Gln	missense
NM_001293191.2:c.521G>A	NP_001280120.1:p.Arg174Gln	missense
NM_001293192.2:c.212G>A	NP_001280121.1:p.Arg71Gln	missense
NM_001293195.2:c.488G>A	NP_001280124.1:p.Arg163Gln	missense
NM_001293196.2:c.212G>A	NP_001280125.1:p.Arg71Gln	missense
NM_001350650.2:c.143G>A	NP_001337579.1:p.Arg48Gln	missense
NM_001350651.2:c.143G>A	NP_001337580.1:p.Arg48Gln	missense
NM_012222.3:c.563G>A	NP_036354.1:p.Arg188Gln	missense
NR_146882.2:n.716G>A		non-coding transcript variant
NR_146883.2:n.565G>A		non-coding transcript variant
NC_000001.11:g.45332767C>T
NC_000001.10:g.45798439C>T
NG_008189.1:g.12704G>A
LRG_220:g.12704G>A
LRG_220t1:c.572G>A	LRG_220p1:p.Arg191Gln

... more HGVS ... less HGVS

Protein change

R191Q, R177Q, R163Q, R174Q, R48Q, R164Q, R178Q, R188Q, R71Q

Other names

p.R191Q:CGG>CAG

Canonical SPDI

NC_000001.11:45332766: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.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00006

The Genome Aggregation Database (gnomAD), exomes 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00006

Exome Aggregation Consortium (ExAC) 0.00005

Links

ClinGen: CA013903 dbSNP: rs369677603 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 (4)	criteria provided, conflicting classifications	Aug 25, 2022	RCV000115768.17
Familial adenomatous polyposis 2	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Feb 19, 2024	RCV000168022.15
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Mar 20, 2024	RCV000212702.9
not specified	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV001192928.2
Familial adenomatous polyposis 2 Neoplasm of stomach Pilomatrixoma	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2018	RCV000765176.2

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 (Oct 10, 2019)	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: SCV001361389.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (1) PubMed: 31159747 Comment: Variant summary: MUTYH c.572G>A (p.Arg191Gln) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Five of … (more) Variant summary: MUTYH c.572G>A (p.Arg191Gln) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251474 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (6.4e-05 vs 0.0046), allowing no conclusion about variant significance. c.572G>A has been reported in the literature in a cohort of individuals under going genetic testing (exact phenotype of the reported individual was not provided)(Tsaousis_2019). This report does not provide an unequivocal conclusion about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions (evaluation after 2014) cite the variant seven times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Likely benign (Mar 21, 2016)	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: SCV000902721.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Uncertain significance (Jan 29, 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: SCV000218674.12 First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 28492532‚ 31159747 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 191 of the MUTYH protein (p.Arg191Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 191 of the MUTYH protein (p.Arg191Gln). This variant is present in population databases (rs369677603, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of MUTYH-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 127846). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 19, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004198805.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Mar 20, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149677.19 First in ClinVar: May 17, 2014 Last updated: Sep 16, 2024	Comment: In silico analysis supports that this missense variant does not alter protein structure/function; Observed in cases and controls in a breast cancer study and in … (more) In silico analysis supports that this missense variant does not alter protein structure/function; Observed in cases and controls in a breast cancer study and in individuals undergoing multigene panel testing due to unspecified familial cancer (PMID: 33471991, 31159747); This variant is associated with the following publications: (PMID: 35982159, 36243179, 31159747, 33939675, 33471991) (less)
Uncertain significance (Apr 09, 2018)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000799307.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018
Uncertain significance (Aug 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	GeneKor MSA Accession: SCV000822075.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pilomatrixoma Familial adenomatous polyposis 2 Gastric cancer Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000896409.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (May 08, 2018)	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: SCV000888319.2 First in ClinVar: Dec 06, 2016 Last updated: Jan 01, 2022
Uncertain significance (Feb 24, 2022)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002532302.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The MUTYH c.572G>A (p.R191Q) variant has been reported in 5/60466 breast cancer cases and 4/53461 healthy controls by a large case-control study (PMID: 33471991). It … (more) The MUTYH c.572G>A (p.R191Q) variant has been reported in 5/60466 breast cancer cases and 4/53461 healthy controls by a large case-control study (PMID: 33471991). It was also observed in an individual undergoing testing for hereditary cancer predisposition (PMID: 31159747). It was observed in 12/10080 chromosomes of the Ashkenazi Jewish subpopulation, with no homozygotes, in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID 32461654). The variant has been reported in ClinVar (Variation ID: 127846). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)	Publications: PubMed (2) PubMed: 33471991‚ 31159747
Uncertain significance (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004025045.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023
Uncertain significance (Aug 25, 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: SCV000183833.9 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 31159747 Comment: The p.R191Q variant (also known as c.572G>A), located in coding exon 7 of the MUTYH gene, results from a G to A substitution at nucleotide … (more) The p.R191Q variant (also known as c.572G>A), located in coding exon 7 of the MUTYH gene, results from a G to A substitution at nucleotide position 572. The arginine at codon 191 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition. (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other 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)
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Comment:

Variant summary: MUTYH c.572G>A (p.Arg191Gln) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251474 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (6.4e-05 vs 0.0046), allowing no conclusion about variant significance. c.572G>A has been reported in the literature in a cohort of individuals under going genetic testing (exact phenotype of the reported individual was not provided)(Tsaousis_2019). This report does not provide an unequivocal conclusion about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions (evaluation after 2014) cite the variant seven times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 191 of the MUTYH protein (p.Arg191Gln). This variant is present in population databases (rs369677603, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of MUTYH-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 127846). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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:

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in cases and controls in a breast cancer study and in individuals undergoing multigene panel testing due to unspecified familial cancer (PMID: 33471991, 31159747); This variant is associated with the following publications: (PMID: 35982159, 36243179, 31159747, 33939675, 33471991)

Comment:

The p.R191Q variant (also known as c.572G>A), located in coding exon 7 of the MUTYH gene, results from a G to A substitution at nucleotide position 572. The arginine at codon 191 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition. (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other 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

Title	Author	Journal	Year	Link
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.	Tsaousis GN	BMC cancer	2019	PMID: 31159747

Text-mined citations for rs369677603 ...

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.488G>A (p.Arg163Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs369677603 ...