VCV000185982.26 - ClinVar

NM_001048174.2(MUTYH):c.953C>G (p.Ser318Trp)

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.

(11)

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.953C>G (p.Ser318Trp)

Variation ID: 185982 Accession: VCV000185982.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.1 1: 45331810 (GRCh38) [ NCBI UCSC ] 1: 45797482 (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 16, 2017	Jun 17, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001048174.2:c.953C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001041639.1:p.Ser318Trp	missense
NM_001128425.2:c.1037C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001121897.1:p.Ser346Trp	missense
NM_001048171.2:c.953C>G	NP_001041636.2:p.Ser318Trp	missense
NM_001048172.2:c.956C>G	NP_001041637.1:p.Ser319Trp	missense
NM_001048173.2:c.953C>G	NP_001041638.1:p.Ser318Trp	missense
NM_001293190.2:c.998C>G	NP_001280119.1:p.Ser333Trp	missense
NM_001293191.2:c.986C>G	NP_001280120.1:p.Ser329Trp	missense
NM_001293192.2:c.677C>G	NP_001280121.1:p.Ser226Trp	missense
NM_001293195.2:c.953C>G	NP_001280124.1:p.Ser318Trp	missense
NM_001293196.2:c.677C>G	NP_001280125.1:p.Ser226Trp	missense
NM_001350650.2:c.608C>G	NP_001337579.1:p.Ser203Trp	missense
NM_001350651.2:c.608C>G	NP_001337580.1:p.Ser203Trp	missense
NM_012222.3:c.1028C>G	NP_036354.1:p.Ser343Trp	missense
NR_146882.2:n.1181C>G		non-coding transcript variant
NR_146883.2:n.1030C>G		non-coding transcript variant
NC_000001.11:g.45331810G>C
NC_000001.10:g.45797482G>C
NG_008189.1:g.13661C>G
LRG_220:g.13661C>G
LRG_220t1:c.1037C>G	LRG_220p1:p.Ser346Trp

... more HGVS ... less HGVS

Protein change

S346W, S332W, S343W, S203W, S226W, S318W, S333W, S319W, S329W

Other names

Canonical SPDI

NC_000001.11:45331809:G:C

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA012006 dbSNP: rs587778538 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	2689	2845

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 (3)	criteria provided, multiple submitters, no conflicts	Jan 18, 2023	RCV000165499.13
Familial adenomatous polyposis 2	Uncertain significance (5)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000203957.15
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 17, 2018	RCV000759877.6
Familial adenomatous polyposis 2 Gastric cancer	Uncertain significance (1)	criteria provided, single submitter	Mar 15, 2022	RCV002492662.2

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 27, 2017)	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: SCV000792412.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017
Uncertain significance (Oct 17, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001778064.1 First in ClinVar: Aug 13, 2021 Last updated: Aug 13, 2021	Comment: Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on … (more) Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function (less)
Uncertain significance (Jun 27, 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: SCV000889516.2 First in ClinVar: Mar 14, 2019 Last updated: Jan 01, 2022
Uncertain significance (Sep 25, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002532197.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The MUTYH c.1037C>G (p.S346W) variant has been reported in heterozygosity in at least one individual with male breast cancer (PMID: 30564557). This variant has also … (more) The MUTYH c.1037C>G (p.S346W) variant has been reported in heterozygosity in at least one individual with male breast cancer (PMID: 30564557). This variant has also been reported in 1/60466 breast cancer cases and 4/53461 healthy controls by a large case-control study (PMID: 33471991). It was observed in 5/108530 chromosomes of the Non-Finnish European subpopulation 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: 185982). 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‚ 30564557
Uncertain significance (Mar 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Gastric cancer Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002791066.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Jul 25, 2023)	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV004031236.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023	Comment: The MUTYH c.1037C>G (p.Ser346Trp) missense change has a maximum subpopulation frequency of 0.0046% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign … (more) The MUTYH c.1037C>G (p.Ser346Trp) missense change has a maximum subpopulation frequency of 0.0046% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in 1 of 503 male breast cancer patients who were negative for alterations in BRCA1/2 (PMID: 30564557). To our knowledge, this variant has not been reported in individuals with MUTYH-associated polyposis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
Uncertain significance (Nov 08, 2022)	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: SCV001356409.3 First in ClinVar: Mar 25, 2020 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 30564557‚ 33471991 Comment: This missense variant replaces serine with tryptophan at codon 346 of the MUTYH protein. Computational prediction tool suggests that this variant may not impact protein … (more) This missense variant replaces serine with tryptophan at codon 346 of the MUTYH protein. Computational prediction tool 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 been reported in an individual affected with male breast cancer (PMID: 30564557). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 4/53461 controls (PMID: 33471991). This variant has been identified in 6/241834 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 (Jan 24, 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: SCV000261495.10 First in ClinVar: Jan 31, 2016 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 28492532‚ 30564557 Comment: This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 346 of the MUTYH protein … (more) This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 346 of the MUTYH protein (p.Ser346Trp). This variant is present in population databases (rs587778538, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 30564557). ClinVar contains an entry for this variant (Variation ID: 185982). 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 disruptive. 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 (Oct 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004835081.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (2) PubMed: 30564557‚ 33471991 Comment: This missense variant replaces serine with tryptophan at codon 346 of the MUTYH protein. Computational prediction tool suggests that this variant may not impact protein … (more) This missense variant replaces serine with tryptophan at codon 346 of the MUTYH protein. Computational prediction tool 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 been reported in an individual affected with male breast cancer (PMID: 30564557). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 4/53461 controls (PMID: 33471991). This variant has been identified in 6/241834 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) Number of individuals with the variant: 2
Uncertain significance (Jan 18, 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: SCV000216230.8 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 30564557 Comment: The p.S346W variant (also known as c.1037C>G), located in coding exon 12 of the MUTYH gene, results from a C to G substitution at nucleotide … (more) The p.S346W variant (also known as c.1037C>G), located in coding exon 12 of the MUTYH gene, results from a C to G substitution at nucleotide position 1037. The serine at codon 346 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration was detected in 1/503 male breast cancer patients who had previously tested negative for BRCA1/2 mutations (Rizzolo P et al. Front Oncol, 2018 Dec;8:583). This amino acid position is poorly 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)
Uncertain significance (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005056056.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
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Comment:

The MUTYH c.1037C>G (p.Ser346Trp) missense change has a maximum subpopulation frequency of 0.0046% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in 1 of 503 male breast cancer patients who were negative for alterations in BRCA1/2 (PMID: 30564557). To our knowledge, this variant has not been reported in individuals with MUTYH-associated polyposis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

Comment:

This missense variant replaces serine with tryptophan at codon 346 of the MUTYH protein. Computational prediction tool 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 been reported in an individual affected with male breast cancer (PMID: 30564557). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 4/53461 controls (PMID: 33471991). This variant has been identified in 6/241834 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:

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 346 of the MUTYH protein (p.Ser346Trp). This variant is present in population databases (rs587778538, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 30564557). ClinVar contains an entry for this variant (Variation ID: 185982). 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 disruptive. 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 serine with tryptophan at codon 346 of the MUTYH protein. Computational prediction tool 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 been reported in an individual affected with male breast cancer (PMID: 30564557). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 4/53461 controls (PMID: 33471991). This variant has been identified in 6/241834 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.S346W variant (also known as c.1037C>G), located in coding exon 12 of the MUTYH gene, results from a C to G substitution at nucleotide position 1037. The serine at codon 346 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration was detected in 1/503 male breast cancer patients who had previously tested negative for BRCA1/2 mutations (Rizzolo P et al. Front Oncol, 2018 Dec;8:583). This amino acid position is poorly 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:

This missense variant replaces serine with tryptophan at codon 346 of the MUTYH protein. Computational prediction tool 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 been reported in an individual affected with male breast cancer (PMID: 30564557). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 4/53461 controls (PMID: 33471991). This variant has been identified in 6/241834 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:

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
Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy.	Rizzolo P	Frontiers in oncology	2018	PMID: 30564557

Text-mined citations for rs587778538 ...

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.953C>G (p.Ser318Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587778538 ...