rs587780751

Positions:

chr1-45332163-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001048174.2(MUTYH):c.849+3A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000898 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 splice_region, intron

Scores

Splicing: ADA: 0.9997

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25U:1

Conservation

PhyloP100: 0.543

Variant links:

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 links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-45332163-T-G is Pathogenic according to our data. Variant chr1-45332163-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 135992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45332163-T-G is described in Lovd as [Pathogenic]. Variant chr1-45332163-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2 linkuse as main transcript	c.849+3A>C		splice_region_variant, intron_variant		ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7 linkuse as main transcript	c.849+3A>C		splice_region_variant, intron_variant		1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 linkuse as main transcript	n.1437+3A>C		splice_region_variant, intron_variant				ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00110

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:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251414

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.000141

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000876

AC:

128

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000921

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.000113

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000112

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000957

Hom.:

Bravo

AF:

0.0000945

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:25Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:13

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change falls in intron 10 of the MUTYH gene. It does not directly change the encoded amino acid sequence of the MUTYH protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587780751, gnomAD 0.01%). This variant has been observed in individual(s) with adenomatous polyposis (PMID: 12853198, 16616356, 19732775, 22773231, 22865608). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of North-Eastern Italy ancestry (PMID: 12853198, 16616356, 19732775, 22773231, 22865608). This variant is also known as c.891+3A>C. ClinVar contains an entry for this variant (Variation ID: 135992). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 10 and introduces a premature termination codon (PMID: 16616356, 22865608; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 30, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	research	Department of Pediatrics, Memorial Sloan Kettering Cancer Center	Dec 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 08, 2016	Variant summary: MUTYH c.933+3A>C variant affects a non-conserved intronic nucleotide. Mutation Taster predicts a damaging outcome for this variant, and 5/5 Alamut algorithms predict the variant to alter normal splicing, which is supported by patient cDNA showing that this variant results in a fusion of exon 9 to exon 11. This variant is found in 8/124162 control chromosomes at a frequency of 0.0000644, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0055902). However, the variant has been cited in numerous CRC patients in the literature. In addition, several diagnostic clinical laboratories and databases classified this variant as pathogenic. Taken together, this is a disease variant and was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 11, 2019	The c.933+3A>C variant in MUTYH has been previously reported in 24 individuals (23 were compound heterozygotes, 1 was a homozygote, and 1 was a heterozygote) with MUTYH-related attenuated familial adenomatous polyposis (FAP)and segregated with disease in 7 affected family members (Sampson 2003, Vogt 2009, Pin 2013). It has also been identified in 0.01% (18/129140) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org).This frequency is low enough to be consistent with the carrier frequency of MUTYH-related attenuated FAP in the general population. This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing and functional studies provide evidence that this variant alters splicing (Pin 2013). In summary, this variant meets criteria to be classified as pathogenic for FAP in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PS3_Moderate, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Oct 10, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 30, 2024	This variant causes an A to C nucleotide substitution at the +3 position of intron 10 of the MUTYH gene. Functional RNA studies have shown that this variant causes skipping of exon 10, resulting in a frameshift and premature stop codon (p.Gly264Trpfs*7) (PMID: 16616356, 22865608). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with MUTYH-associated polyposis as homozygous or in trans with another pathogenic variant (PMID: 12853198, 16616356, 18495334, 19732775, 20618354, 22773231, 22865608, 23108399, 27829682), colorectal cancer (PMID: 28135145, 29478780, 35668106), breast cancer (PMID: 30564557, 33606809), or pancreatic ductal adenocarcinoma (PMID: 34506673). This variant is considered a founder mutation in Western Europe (PMID: 22865608). This variant has been identified in 21/282792 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	Baylor Genetics	Mar 27, 2024	- -

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2021	Splice site variant demonstrated to result in exon 10 skipping in a gene for which loss-of-function is a known mechanism of disease (Kanter-Smoler 2006, Pin 2013); Published functional studies demonstrate a damaging effect: defects in glycosylase activity (Ruggieri 2013); This variant is associated with the following publications: (PMID: 20618354, 30233642, 30604180, 12853198, 26202870, 25980754, 23108399, 22865608, 19732775, 27194394, 26798439, 27829682, 26446593, 27799157, 23891399, 16616356, 16140997, 18495334, 22976915, 29406563, 22773231, 31277343, 32088803, 33258288, 30787465, 33606809, 34026625, 34704405, 34485163) -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Apr 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 05, 2020	PVS1, PS3, PM3, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 27, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 19, 2023	The MUTYH c.933+3A>C variant has been reported in the published literature in homozygous and compound heterozygous individuals with MUTYH-Associated Polyposis (MAP) (PMIDs: 32088803 (2020), 27829682 (2016), 22865608 (2013), 19732775 (2009)) and colon cancer (PMIDs: 30604180 (2019), 28135145 (2017), 22773231 (2013), 12853198 (2003)). Functional studies show this variant causes altered exon 10 splicing (PMID: 22865608 (2013), 16616356 (2006)), as well as reduced protein expression and abolished DNA glycosylase activity (PMID: 23108399 (2013)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper MUTYH mRNA splicing. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	MUTYH: PVS1, PM3, PM2:Supporting, PS3:Supporting -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 26, 2024	The c.933+3A>C intronic pathogenic mutation results from an A to C substitution 3 nucleotides after coding exon 10 in the MUTYH gene. This alteration has been well described in the literature, and has been reported in both the homozygous and compound heterozygous state with other MUTYH alterations in multiple individuals with MUTYH-associated polyposis (Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85; Urso ED et al. Surg Endosc, 2013 Jan;27:207-13; Ricci MT et al. J Hum Genet, 2017 Feb;62:309-315; Sutcliffe EG et al. Fam Cancer, 2019 04;18:203-209; Daans CG et al. Fam Cancer, 2020 04;19:183-187; Ambry internal data). This alteration has also been described as a founder mutation in the Northeastern Italian and German populations (Pin E et al. Int. J. Cancer. 2013 Mar;132:1060-9). Of note, this alteration is also designated as c.891+3A>C in published literature. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 11, 2023	This variant causes an A to C nucleotide substitution at the +3 position of intron 10 of the MUTYH gene. Functional RNA studies have shown that this variant causes skipping of exon 10, resulting in a frameshift and premature stop codon (p.Gly264Trpfs*7) (PMID: 16616356, 22865608). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with MUTYH-associated polyposis as homozygous or in trans with another pathogenic variant (PMID: 12853198, 16616356, 18495334, 19732775, 20618354, 22773231, 22865608, 23108399, 27829682), colorectal cancer (PMID: 28135145, 29478780, 35668106), breast cancer (PMID: 30564557, 33606809), or pancreatic ductal adenocarcinoma (PMID: 34506673). This variant is considered a founder mutation in Western Europe (PMID: 22865608). This variant has been identified in 21/282792 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Dec 05, 2023	- -

Carcinoma of colon

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MUTYH c.933+3A>C variant was identified in 27 of 1210 proband chromosomes (frequency: 0.022) from individuals or families with polyposis coli or colorectal cancer, and was not identified in 340 control chromosomes from healthy individuals (Kanter-Smoler 2006, Nielsen 2005, Pin 2013, Sampson 2003, Vogt 2009). Most of the probands described in these studies were heterozygous for the variant and had a second MUTYH variant (compound heterozygotes); while one proband from a study by Pin (2013) was homozygous for the variant. The variant was also identified in the â€šÃ„ÃºInSiGHT Colon Cancer Databaseâ€šÃ„Ã¹, HGMD, UMD (33X as a causal variant) and the ClinVar database (with â€šÃ„Ãºpathogenicâ€šÃ„Ã¹ clinical significance, submitted by Ambry Genetics and Invitae). The c.933+3A>C variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. Four out of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. Analysis of mRNA in functional studies by Ruggieri (2013) and Pin (2013) have shown that this variant affects splicing, resulting skipping of exon 10 in mRNA transcripts. Protein analysis from these studies demonstrated reduced levels of MUTYH protein, although the amount of protein varied greatly, depending on the second MUTYH mutation in compound heterozygotes. Pin (2013) notes that traces of full-length transcripts and wild-type protein were found in cells homozygous for the variant, suggesting some transcripts may escape from aberrant splicing. The authors of this study found this in agreement with clinical findings in a homozygous proband, who presented with a relatively mild phenotype (attenuated polyposis). In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

MUTYH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2024

The MUTYH c.933+3A>C variant is predicted to interfere with splicing. This variant, either in a homozygous state or compound heterozygous state with a second pathogenic mutation, has been reported to be causative for autosomal recessive MUTYH-associated polyposis (Sampson et al. 2003. PubMed ID: 12853198, reported as 891+3A>C; Pin et al. 2013. PubMed ID: 22865608; Ricci et al. 2017. PubMed ID: 27829682). It is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135992/). This variant is interpreted as pathogenic. -

Colon cancer

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

0.96

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.96

Position offset: 3

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over