rs374950566

Variant names:

• chr1-45332215-G-A
• rs374950566
• NM_001048174.2:c.800C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_001048174.2(MUTYH):​c.800C>T​(p.Pro267Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P267S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26
• Conservation: PhyloP100: 7.74
• Publications: 29 publications found

Genes affected

MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]

MUTYH Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
• colorectal cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 56 uncertain in NM_001048174.2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 1-45332215-G-A is Pathogenic according to our data. Variant chr1-45332215-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 185242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.800C>T	p.Pro267Leu	missense_variant	Exon 10 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.800C>T	p.Pro267Leu	missense_variant	Exon 10 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1388C>T		non_coding_transcript_exon_variant	Exon 14 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251116 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461848 Hom.: 0 Cov.: 36 AF XY: 0.0000110 AC XY: 8 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111982

Other (OTH) AF: 0.0000662 AC: 4 AN: 60388

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000127 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:10

Feb 11, 2019

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MUTYH: PM3:Strong, PM1, PM2, PS3:Moderate -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MUTYH c.884C>T (p.Pro295Leu) variant has been reported in the published literature in individuals affected with polyposis (PMIDs: 16941501 (2006), 34326862 (2021), 35418818 (2022)), colorectal cancer (PMIDs: 29406563 (2018), 32283892 (2020), 35418818 (2022)), and others affected or at risk for various cancers (PMIDs: 34637943 (2021), 35734982 (2022)). Functional studies showed this variant had severely defective DNA binding and defective glycosylase activity (PMIDs: 18534194 (2008), 26377631 (2015)). It was also unable to suppress spontaneous mutations compared to the wild-type (PMID: 25820570 (2015)). The frequency of this variant in the general population, 0.000026 (3/113520 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Aug 25, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: defective DNA binding capability, compromised base excision activity, and near absent glycosylase activity (Ali et al., 2008; Brinkmeyer et al., 2015; Komine et al., 2015); Observed in both the homozygous and compound heterozygous state in individuals affected with MUTYH Associated Polyposis (Jones et al., 2009; Nielsen et al., 2009; Vogt et al., 2009; Morak et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25820570, 18534194, 30604180, 34637943, 16941501, 19032956, 19394335, 20618354, 23507534, 26377631, 19732775, 31159747, 32231684, 30291343, 32283892, 34426522, 31589614, 30787465, 29406563, 35089076, 33980423, 34271781, 35238777, 35418818, 17219385, 36368126, 35734982, 35261632, 11092888, 11160897, 16879101, 20816984, 37065479, 37453313, 16557584) -

Jun 17, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial adenomatous polyposis 2 Pathogenic:10

Apr 28, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MUTYH c.884C>T (p.Pro295Leu), also referred to as p.Pro281Leu, results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251116 control chromosomes. c.884C>T has been observed as a biallelic genotype in individuals affected with MUTYH-Associated Polyposis and in the heterozygous state in individuals affected with breast cancer and/or other types of cancer (e.g. Vogt_2009, Arslan_Ates_2022). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function and have found that the variant has severely defective glycosylase activity as well as DNA binding activity (e.g. Ali_2008, Komine_2015, Brinkmeyer_2015). The following publications have been ascertained in the context of this evaluation (PMID: 18534194, 35734982, 26377631, 25820570, 19732775). ClinVar contains an entry for this variant (Variation ID: 185242). Based on the evidence outlined above, the variant was classified as pathogenic for MUTYH-Associated Polyposis and Hereditary Breast And Ovarian Cancer Syndrome. -

Dec 22, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 26, 2023

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 295 of the MUTYH protein (p.Pro295Leu). This variant is present in population databases (rs374950566, gnomAD 0.004%). This missense change has been observed in individual(s) with polyposis and/or colorectal cancer (PMID: 19732775; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 185242). 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. Experimental studies have shown that this missense change affects MUTYH function (PMID: 18534194, 25820570, 26377631). For these reasons, this variant has been classified as Pathogenic. -

Jul 29, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with leucine at codon 295 in the FeS cluster domain of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes deficient mismatch repair and DNA-binding (PMID: 18534194, 26377631). This variant has been reported in the homozygous state or compound heterozygous state in individuals affected with MUTYH-associated polyposis (PMID: 16557584, 16941501, 17219385, 19032956, 20618354, 29406563, 35238777). This variant has also been reported in individuals affected with colorectal cancer (PMID: 32658311, 33980423, 34271781) and breast cancer (PMID: 33471991, 33980423, 35089076; DOI: 10.14744/ejmo.2022.88057). This variant has been identified in 3/251116 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Jun 30, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3,PM3_STR,PM2_SUP,PP3 -

Jan 31, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 20, 2023

Human Genetics Bochum, Ruhr University Bochum

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used to clasify this variant:PS3, PP3_STR, PS4_MOD, PM2_SUP -

Apr 01, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 26, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:4

Jan 09, 2021

GeneKor MSA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense mutation results in the substitution of amino acid Proline with Leucine at codon 295 of the MUTYH protein. The proline residue is highly conserved and there is physiochemical difference between proline and Leucine (Grantham Score 98). This variant is present at low frequency in population databases (rs374950566, ExAC <0.01%). Additionally, it has been reported in the literature in individuals affected with polyposis and/or colorectal cancer (PMID: 19732775, PMID: 19394335, PMID: 19032956, PMID: 17219385, PMID: 16557584). Experimental studies have confirmed the disrupting effect of this variant in the protein function (PMID: 25820570, PMID: 26377631). The mutation database ClinVar contains entries for this variant (Variation ID: 185242). -

Feb 02, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with leucine at codon 295 in the FeS cluster domain of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant has a deleterious impact on mismatch repair and DNA-binding (PMID: 18534194, 26377631). This variant has been reported in the homozygous state or compound heterozygous state in individuals affected with MUTYH-associated polyposis (PMID: 16557584, 16941501, 17219385, 19032956, 20618354, 29406563, 35238777). This variant has also been reported in individuals affected with colorectal cancer (PMID: 32658311, 33980423, 34271781) and breast cancer (PMID: 33471991, 33980423, 35089076, 35734982, 36368126; DOI: 10.14744/ejmo.2022.88057). This variant has been identified in 3/251116 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Jun 05, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P295L pathogenic mutation (also known as c.884C>T), located in coding exon 10 of the MUTYH gene, results from a C to T substitution at nucleotide position 884. The proline at codon 295 is replaced by leucine, an amino acid with similar properties. This mutation has been described in multiple patients with adenomatous polyposis who were homozygous for this mutation or compound heterozygous for this and another pathogenic MUTYH alteration (Lejeune S et al. Hum. Mutat., 2006 Oct;27:1064; Vogt S et al. Gastroenterology, 2009 Dec;137:1976-85.e1-10; Jones N et al. Gastroenterology, 2009 Aug;137:489-94, 494.e1; quiz 725-6; Morak M et al. Clin. Genet., 2010 Oct;78:353-63; Croitoru ME et al. J Surg Oncol, 2007 May;95:499-506; Yanus GA et al. Clin. Genet., 2018 May;93:1015-1021). In vitro functional studies demonstrate DNA binding activity and base excision repair activity are severely defective (Ali M et al. Gastroenterology 2008 Aug; 135(2):499-507; Komine K et al. Hum. Mutat., 2015 Jul;36:704-11). Of note, this alteration is also described as p.P281L (c.842C>T) in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as a pathogenic mutation. -

Feb 05, 2022

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Carcinoma of colon Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MUTYH p.Pro295Leu variant has been reported in 5 probands with multiple adenoma polyposis (MAP) (Lejeune 2006, Jones 2009). All of these probands were homozygous or compound heterozygous. The variant has also been found in a homozygous state in an individual with MAP (Jones 2009). The MUTYH p.Pro295Leu variant was identified in 8 of 1126 proband chromosomes (frequency: 0.007 from individuals or families with multiple adenoma polyposis (MAP) and was not identified in 100 control chromosomes from healthy individuals (Aretz 2006, Croitoru 2007, Lejeune 2006, Vogt 2009); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also identified in HGMD, “InSiGHT Colon Cancer Database” and UMD (4X as a causal variant). The variant was identified by the Exome Variant Server project in 1 of 4405 African American alleles (frequency: 0.0002), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Pro295 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) suggest that the p.Pro295Leu variant may impact the protein. Lejeune (2006) notes that this variant is located in an important functional domain involved in substrate binding and catalysis, and an in vitro functional study demonstrated that the p.Pro295Leu variant was severely defective in both glycosylase and DNA binding (Ali 2008). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Breast carcinoma Pathogenic:1

Aug 08, 2021

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	.;.;.;.;.;D;.;.;.;D;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	.;.;.;.;.;H;.;.;.;.;.;.
PhyloP100		7.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-9.3	D;D;D;D;D;D;D;D;D;.;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;D;.;D;.;.;.
Vest4		0.84
MVP		0.99
MPC		0.55
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		0.0036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs374950566; hg19: chr1-45797887;