rs138775799

chr1-45333472-G-Achr1-45333472-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001048174.2(MUTYH):c.205C>T(p.Arg69Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000682 in 1,614,052 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MUTYH NM_001048174.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 6.89

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-45333472-G-A is Pathogenic according to our data. Variant chr1-45333472-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 140827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45333472-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-45333472-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.289C>T	p.Arg97Ter	stop_gained	3/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.205C>T	p.Arg69Ter	stop_gained	3/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.289C>T	p.Arg97Ter	stop_gained	3/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.205C>T	p.Arg69Ter	stop_gained	3/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251488 Hom.: 0 AF XY: 0.0000221 AC XY: 3 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: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461884 Hom.: 0 Cov.: 35 AF XY: 0.00000825 AC XY: 6 AN XY: 727246

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: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74338

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000272 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The MUTYH c.247C>T (p.Arg83Ter) variant, also reported as c.289C>T (p.Arg97Ter), is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg83Ter variant has been reported in at least six studies in which it is found in at least six individuals with MYH-associated polyposis, including in two in a homozygous state, in two in a compound heterozygous state with a missense variant on the second allele, and in two in a heterozygous state with a second variant remaining undetected (Sieber et al. 2003; Aretz et al. 2006; Olschwang et al. 2007; Steinke et al. 2008; Filipe et al. 2009; Morak et al. 2010). One of the individuals who was heterozygous for the p.Arg83Ter variant also carried a known pathogenic variant in the MSH6 gene in a heterozygous state (Steinke et al. 2008). The p.Arg83Ter variant was absent from 446 control chromosomes but is reported at a frequency of 0.00023 in the African American population from the Exome Sequencing Project. This is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. In vitro functional studies demonstrated that the adenine DNA glycosylase activity of the p.Arg83Ter variant protein was similar to background levels and severely impaired compared to wild type (Goto et al. 2010). Based on the evidence from the literature and the potential impact of stop-gained variants, the p.Arg83Ter variant is classified as pathogenic for MYH-associated polyposis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 09, 2017	Variant summary: The MUTYH c.289C>T (p.Arg97X) variant results in a premature termination codon, predicted to cause a truncated or absent MUTYH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/277650 control chromosomes at a frequency of 0.0000144, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). This variant has been reported in multiple affected individuals. Functional assay showed variant with extremely severely defective DNA glycosylase activity (Goto_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 13, 2016	The p.Arg94X (also known as p.Arg97X or p.Arg83X) variant in MUTYH has been previously reported as compound heterozygous in one individual with MUTYH-related attenuated familial adenomatous polyposis (FAP); as heterozygous in one individual with FAP; and as double heterozygous with a disease causing MSH6 variant in one individual with HNPCC (Seiber 2003, Steinke 2008, Vogt 2009). It has also been identified in 2/16512 of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://-exac.broadinstitute.org; dbSNP rs138775799). This frequency is low enough to be consistent with the frequency of MUTYH-related attenuated FAP in the general population. This nonsense variant leads to a premature termination codon at position 94, which is predicted to lead to a truncated or absent protein. Homozygous loss of function of the MUTYH gene is an established disease mechanism in individuals with MUTYH-related attenuated FAP. In vitro functional studies provide some evidence that the p.Arg94X variant may impact protein function (Goto 2010). In summary, this variant meets our criteria to be classified as pathogenic for MUTYH-related attenuated FAP in an autosomal recessive manner based on the predicted impact of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Arg97*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). This variant is present in population databases (rs138775799, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and/or MUTYH-associated polyposis (PMID: 12606733, 17949294, 19732775, 19793053, 20618354). This variant is also known as R83X and R69X. ClinVar contains an entry for this variant (Variation ID: 140827). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This variant changes 1 nucleotide in exon 3 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported as homozygous in an individual affected with polyposis and colorectal cancer (PMID: 19793053; referred to as R83X in this article) and as compound heterozygous with a known pathogenic variant p.Tyr179Cys in an individual affected with polyposis (PMID: 20618354). This variant has been identified in 4/282870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: impaired glycosylase activity (Goto 2010); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19032956, 16134146, 12606733, 19793053, 17949294, 16557584, 18301448, 19732775, 25525159, 20848659, 23605219, 20618354, 19394335, 19414147, 19725997, 21235684, 30604180, 31589614, 32029870, 30787465) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 29, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 18, 2023	This variant changes 1 nucleotide in exon 3 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported as homozygous in an individual affected with polyposis and colorectal cancer (PMID: 19793053; referred to as R83X in this article) and as compound heterozygous with a known pathogenic variant p.Tyr179Cys in an individual affected with polyposis (PMID: 20618354). This variant has been identified in 4/282870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 03, 2021	The p.R97* pathogenic mutation (also known as c.289C>T), located in coding exon 3 of the MUTYH gene, results from a C to T substitution at nucleotide position 289. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation has been previously reported in individuals with MUTYH-associated polyposis (MAP) (Sieber OM et al. N. Engl. J. Med. 2003 Feb;348(9):791-9; Vogt S et al. Gastroenterology. 2009 Dec;137(6):1976-85). Of note, this alteration is also designated as R83X and c.247C>T in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;D;D;D;D
Vest4		0.92
GERP RS		4.4

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: rs138775799; hg19: chr1-45799144; COSMIC: COSV58343886; COSMIC: COSV58343886;