rs747993448

chr1-45332795-G-Achr1-45332795-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001048174.2(MUTYH):c.460C>T(p.Arg154Cys) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R154G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:17 B:1
• Conservation: PhyloP100: 2.53

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-45332794-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 182689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187280.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=12, Benign=1, Likely_pathogenic=4}. Variant chr1-45332795-G-A is described in Lovd as [Pathogenic]. Variant chr1-45332795-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.544C>T	p.Arg182Cys	missense_variant	7/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.460C>T	p.Arg154Cys	missense_variant	7/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.544C>T	p.Arg182Cys	missense_variant	7/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.460C>T	p.Arg154Cys	missense_variant	7/16	1	NM_001048174.2	A1

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

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251458 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000647 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:17 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:9

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 26, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM3 very strong, PP1 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 06, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 02, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 17, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 20, 2019	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2023	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) -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	MUTYH: PM2, PM3, PS3:Moderate -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 25, 2022	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 alteration has been previously identified in conjunction with the c.1437_1439del MUTYH mutation in an individual with 100-1000 polyps and with the p.Y179C MUTYH mutation in two unrelated patients with colon cancer and multiple polyps (De Rosa M et al. Dis Colon Rectum. 2009 Feb;52(2):268-74; Wang L et al. Gastroenterology. 2004 Jul;127(1):9-16; Cattaneo F et al. Genet. Med. 2007 Dec;9(12):836-41). Furthermore, this alteration was reportedly determined to be detected in trans with a pathogenic MUTYH mutation in one patient (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. In addition, a different disease causing mutation, p.R182H, has also been described at this same location. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 20, 2023	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. -

Pilomatrixoma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Nov 15, 2019

PSx1, PMx1, PPx3 -

Ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 01, 2022

- -

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
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;N;N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs747993448; hg19: chr1-45798467; COSMIC: COSV58343464; COSMIC: COSV58343464;