rs747993448

Variant names:

• chr1-45332795-G-A
• rs747993448
• NM_001128425.2:c.544C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-45332795-G-A
• chr1-45332795-G-C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_001128425.2(MUTYH):​c.544C>T​(p.Arg182Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R182G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MUTYH NM_001128425.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 B:1
• Conservation: PhyloP100: 2.53
• Publications: 18 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 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 47 uncertain in NM_001128425.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-45332795-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 940199.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 1-45332795-G-A is Pathogenic according to our data. Variant chr1-45332795-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 187280.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_001128425.2	c.544C>T	p.Arg182Cys	missense_variant	Exon 7 of 16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.460C>T	p.Arg154Cys	missense_variant	Exon 7 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.544C>T	p.Arg182Cys	missense_variant	Exon 7 of 16		NM_001128425.2	ENSP00000518552.2
MUTYH	ENST00000456914.7	c.460C>T	p.Arg154Cys	missense_variant	Exon 7 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1048C>T		non_coding_transcript_exon_variant	Exon 11 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251458 AF XY: 0.00000736

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461878 Hom.: 0 Cov.: 36 AF XY: 0.00000825 AC XY: 6 AN XY: 727240

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74462

African (AFR) AF: 0.00 AC: 0 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.0000303 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:9

Aug 26, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM3 very strong, PP1 supporting -

Sep 23, 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 arginine with cysteine at codon 182 of the MUTYH protein. This variant is also known as c.502C>T (p.Arg168Cys) in the literature based on a different transcript (NM_001048171). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that the mutant protein is unable to complement MutY-deficient bacterial cells (PMID: 25820570). This variant has been reported in individuals affected with multiple adenomatous polyposis in compound heterozygous state with a known pathogenic variant (PMID: 15236166, 16890597, 18091433). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same amino acid position, NM_001128425.2:c.545G>A (p.Arg182His) (a.k.a. NM_001048174.2:c.461G>A (p.Arg154His)) is known to be disease-causing (ClinVar variation ID: 182689), indicating that arginine at this position is important for MUTYH function. Based on the available evidence, this variant is classified as Pathogenic. -

Feb 06, 2023

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.544C>T (p.Arg182Cys) results in a non-conservative amino acid change located in the HhH-GPD domain(IPR003265) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251458 control chromosomes (gnomAD). c.544C>T has been reported in the literature in individuals affected with MUTYH-Associated Polyposis and colorectal cancer (e.g. Dell_2021, Di Gregorio_2006, Morak_2010, Wang_2004). These data indicate that the variant is likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function and demonstrated that this missense resulted in deficient function in a bacterial complementation assay (Komine_2015). Another variant altering the same amino acid (p.R182H) have been reported in affected individuals, suggesting a critical role for this residue (HGMD). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 20, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2018

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2016

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. -

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 182 of the MUTYH protein (p.Arg182Cys). This variant is present in population databases (rs747993448, gnomAD 0.0009%). This missense change has been observed in individual(s) with MUTYH-associated adenomatous polyposis and colorectal cancer (PMID: 15236166, 16890597, 18091433, 18301448, 19279422, 21195604). This variant is also known as p.Arg168Cys. ClinVar contains an entry for this variant (Variation ID: 187280). 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: 15236166, 25820570). This variant disrupts the p.Arg182 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15236166, 20848659, 23322991, 25820570). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:5

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MUTYH p.Arg182Cys variant was identified in 5 of 1204 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancer, and was not identified in 2444 control chromosomes from healthy individuals (Cattaneo 2007, De Rosa 2009, Di Gregorio 2006, Olschwang 2007, Steinke 2008). The variant was also identified in dbSNP (ID: rs747993448) as “With Pathogenic allele”, Clinvitae database (classified as pathogenic by Invitae and likely pathogenic by ClinVar), InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classified as pathogenic by Ambry Genetics and Invitae; classified as likely pathogenic by GenDx) and UMD (2x with a “likely causal” classification). In UMD the variant was identified with a co-occurring pathogenic MUTYH variant (c.494A>G, p.Tyr165Cys) increasing the likelihood that the variant has clinical significance. The p.Arg182 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In addition, the variant was identified in patients as one of the biallelic missense variants along with: c.494A>G, p.Tyr165Cys predicted to severely impair the MUTYH protein function (Cattaneo 2007) and c.1395_97delGGA, p.466delE in a patient with classical polyposis phenotype with recessive inheritance (De Rosa 2009). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MUTYH: PM2, PM3, PS3:Moderate -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: defective glycolase activity (Komine et al., 2015); 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: 17949294, 21777424, 35545820, 18301448, 19506731, 16890597, 18091433, 15236166, 21195604, 19279422, 27829682, 16042573, 30787465, 25525159, 32761968, 34704405, 25820570) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Apr 20, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 182 of the MUTYH protein. This variant is also known as c.502C>T (p.Arg168Cys) in the literature based on a different transcript (NM_001048171). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that the mutant protein is unable to complement MutY-deficient bacterial cells (PMID: 25820570). This variant has been reported in individuals affected with multiple adenomatous polyposis in compound heterozygous state with a known pathogenic variant (PMID: 15236166, 16890597, 18091433). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same amino acid position, NM_001128425.2:c.545G>A (p.Arg182His) (a.k.a. NM_001048174.2:c.461G>A (p.Arg154His)) is known to be disease-causing (ClinVar Variation ID: 182689), indicating that arginine at this position is important for MUTYH function. Based on the available evidence, this variant is classified as Pathogenic. -

Feb 10, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R182C pathogenic mutation (also known as c.544C>T), located in coding exon 7 of the MUTYH gene, results from a C to T substitution at nucleotide position 544. The arginine at codon 182 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been identified in the homozygous state and/or in conjunction with other MUTYH variant(s) in individual(s) who met clinical criteria for MUTYH-associated polyposis; in at least one instance, the variants were identified in trans (Wang L et al. Gastroenterology. 2004 Jul;127(1):9-16; Cattaneo F et al. Genet. Med. 2007 Dec;9(12):836-41; De Rosa M et al. Dis Colon Rectum. 2009 Feb;52(2):268-74; Universal Mutation Database [available from www.umd.be]). This alteration has also been identified in a monoallelic state in two individuals with colorectal cancer and/or adenomatous polyps, both of whom met Amsterdam criteria (Morak M et al. Eur. J. Cancer. 2011 May;47(7):1046-55; Steinke V et al. Eur. J. Hum. Genet. 2008 May; 16(5):587-92). A functional complementation assay classified this alteration as defective (Komine K et al. Hum Mutat. 2015 Jul;36(7):704-11). Of note, this mutation is also designated as p.R168C in published literature. Other variant(s) at the same codon, p.R182H (c.545G>A), have been identified in individual(s) with features consistent with MUTYH-associated polyposis (Isidro et al. Hum Mutat 2004 Oct; 24(4):353-4; Di Gregorio et al. Gastroenterology 2006 Aug; 131(2):439-44; Aretz et al. Int J Cancer 2006 Aug 15;119(4): 807-14; Jones N et al. Gastroenterology. 2009 Aug;137(2):489-94, 494.e1; Morak M et al. Clin Genet. 2010 Oct;78(4):353-63). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Pilomatrixoma Pathogenic:1

Nov 15, 2019

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PSx1, PMx1, PPx3 -

Ovarian cancer Benign:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance: Benign

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	.;.;.;.;.;D;.;.;.;D;.;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	4.9	.;.;.;.;.;H;.;.;.;.;.;.
PhyloP100		2.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.4	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;D;.;D;.;.;.
Vest4		0.99
MVP		0.99
MPC		0.64
ClinPred		1.0	D
GERP RS		2.9
Varity_R		0.98
gMVP		0.85
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: rs747993448; hg19: chr1-45798467; COSMIC: COSV58343464; COSMIC: COSV58343464;