VCV000231029.38 - ClinVar

NM_001048174.2(MUTYH):c.160T>C (p.Ser54Pro)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(9); Likely benign(1)

10 out of 10 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001048174.2(MUTYH):c.160T>C (p.Ser54Pro)

Variation ID: 231029 Accession: VCV000231029.38

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.1 1: 45333517 (GRCh38) [ NCBI UCSC ] 1: 45799189 (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	Oct 5, 2025	Sep 9, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_001048174.2:c.160T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001041639.1:p.Ser54Pro	missense
NM_001128425.2:c.244T>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001121897.1:p.Ser82Pro	missense
NM_001048171.2:c.160T>C	NP_001041636.2:p.Ser54Pro	missense
NM_001048172.2:c.163T>C	NP_001041637.1:p.Ser55Pro	missense
NM_001048173.2:c.160T>C	NP_001041638.1:p.Ser54Pro	missense
NM_001293190.2:c.205T>C	NP_001280119.1:p.Ser69Pro	missense
NM_001293191.2:c.193T>C	NP_001280120.1:p.Ser65Pro	missense
NM_001293192.2:c.-97-20T>C		intron variant
NM_001293195.2:c.160T>C	NP_001280124.1:p.Ser54Pro	missense
NM_001293196.2:c.-97-20T>C		intron variant
NM_001350650.2:c.-112T>C		5 prime UTR
NM_001350651.2:c.-92-20T>C		intron variant
NM_012222.3:c.235T>C	NP_036354.1:p.Ser79Pro	missense
NR_146882.2:n.388T>C		non-coding transcript variant
NR_146883.2:n.311T>C		non-coding transcript variant
NC_000001.11:g.45333517A>G
NC_000001.10:g.45799189A>G
NG_008189.1:g.11954T>C
LRG_220:g.11954T>C
LRG_220t1:c.244T>C	LRG_220p1:p.Ser82Pro

... more HGVS ... less HGVS

Protein change

S82P, S79P, S54P, S55P, S65P, S69P

Other names

Canonical SPDI

NC_000001.11:45333516:A:G

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.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA057146 dbSNP: rs773198648 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		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	3948	4112

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	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Nov 20, 2024	RCV000525881.16
Hereditary cancer-predisposing syndrome	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Sep 9, 2025	RCV000218436.17
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 14, 2023	RCV000235580.7
not specified	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Apr 15, 2025	RCV002267956.8

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.	Expand all rows Collapse all rows 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 (Apr 24, 2019) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Not Provided	GeneDx Accession: SCV000292712.10 First in ClinVar: Jul 24, 2016 Last updated: Dec 06, 2016	Comment: show Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32854451) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (Sep 09, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV000274756.10 First in ClinVar: May 29, 2016 Last updated: Oct 05, 2025	Comment: show This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Mar 19, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Sema4 Curation Guidelines)	Hereditary cancer-predisposing syndrome	Sema4, Sema4 Accession: SCV002532271.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The MUTYH c.244T>C (p.S82P) has been reported in in 1/60466 breast cancer cases and 0/53461 healthy controls by a large case-control study (PMID: 33471991). This … (more) The MUTYH c.244T>C (p.S82P) has been reported in in 1/60466 breast cancer cases and 0/53461 healthy controls by a large case-control study (PMID: 33471991). This variant was observed in 3/251464 chromosomes 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: 231029). 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. Based on the current evidence available, this variant is interpreted as a variant of uncertain significance. (less)	Publications: PubMed (1) PubMed: 33471991 Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Uncertain significance (Feb 14, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria)	not provided	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001470570.3 First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024	Publications: PubMed (2) PubMed: 33471991‚ 32854451 Comment: show The frequency of this variant in the general population, 0.000012 (3/251464 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. The variant has been reported in individuals with breast cancer (PMIDs: 32854451 (2020) and 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ MUTYH)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain Significance (Dec 01, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Familial adenomatous polyposis 2 (Autosomal recessive inheritance)	All of Us Research Program, National Institutes of Health Accession: SCV004838064.1 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)	Comment: show This missense variant replaces serine with proline at codon 82 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251464 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 4 Zygosity: Single Heterozygote

Uncertain significance (Mar 24, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Familial adenomatous polyposis 2	Baylor Genetics Accession: SCV004198819.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain significance (Nov 20, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Familial adenomatous polyposis 2	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000639303.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 25, 2025	Publications: PubMed (1) PubMed: 28492532 Comment: show This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 82 of the MUTYH protein (p.Ser82Pro). This variant is present in population databases (rs773198648, gnomAD 0.003%). 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: 231029). 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Mar 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not specified	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002552528.5 First in ClinVar: Jul 28, 2022 Last updated: Mar 11, 2025	Publications: PubMed (1) PubMed: 32854451 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jan 24, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary cancer-predisposing syndrome	Color Diagnostics, LLC DBA Color Health Accession: SCV000690547.6 First in ClinVar: Feb 19, 2018 Last updated: May 03, 2025	Comment: show This missense variant replaces serine with proline at codon 82 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function. 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 3/251464 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Uncertain significance (Apr 15, 2025) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV006073565.2 First in ClinVar: May 03, 2025 Last updated: Jun 29, 2025	Publications: PubMed (1) PubMed: 32854451 Comment: show Variant summary: MUTYH c.244T>C (p.Ser82Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251464 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.244T>C has been observed in individuals affected with breast cancer (e.g., Fanale_2020). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32854451). ClinVar contains an entry for this variant (Variation ID: 231029). Based on the evidence outlined above, the variant was classified as uncertain significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

The frequency of this variant in the general population, 0.000012 (3/251464 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. The variant has been reported in individuals with breast cancer (PMIDs: 32854451 (2020) and 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ MUTYH)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

This missense variant replaces serine with proline at codon 82 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251464 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 proline, which is neutral and non-polar, at codon 82 of the MUTYH protein (p.Ser82Pro). This variant is present in population databases (rs773198648, gnomAD 0.003%). 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: 231029). 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 serine with proline at codon 82 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function. 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 3/251464 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:

Variant summary: MUTYH c.244T>C (p.Ser82Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251464 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.244T>C has been observed in individuals affected with breast cancer (e.g., Fanale_2020). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32854451). ClinVar contains an entry for this variant (Variation ID: 231029). Based on the evidence outlined above, the variant was classified as uncertain significance.

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
Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2.	Fanale D	Cancers	2020	PMID: 32854451

Text-mined citations for rs773198648 ...

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 Oct 05, 2025

ClinVar Genomic variation as it relates to human health

NM_001048174.2(MUTYH):c.160T>C (p.Ser54Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Text-mined citations for rs773198648 ...