rs587780751

Variant names:

• chr1-45332163-T-G
• rs587780751
• NM_001048174.2:c.849+3A>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_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:26 U:1
• Conservation: PhyloP100: 0.543

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]

ENSG00000288208 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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 rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.849+3A>C		splice_region_variant, intron_variant	Intron 10 of 15	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.849+3A>C		splice_region_variant, intron_variant	Intron 10 of 15	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1437+3A>C		splice_region_variant, intron_variant	Intron 14 of 20			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152158 Hom.: 0 Cov.: 33

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: 19 AN: 251414 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135900

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.: 0 Cov.: 36 AF XY: 0.0000921 AC XY: 67 AN XY: 727244

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: 17 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74328

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.: 0

Bravo AF: 0.0000945

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:13

Dec 11, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 18, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered 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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 16616356, 22865608; internal data). For these reasons, this variant has been classified as Pathogenic. -

May 30, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 30, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2016

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.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. -

Jun 29, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 02, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2020

Department of Pediatrics, Memorial Sloan Kettering Cancer Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:7

Dec 19, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 27, 2020

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 05, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS3, PM3, PP3, PP5 -

Dec 22, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MUTYH: PVS1, PM3, PM2:Supporting, PS3:Supporting -

Apr 03, 2020

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Oct 26, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 11, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 05, 2023

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 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 “InSiGHT Colon Cancer Database”, HGMD, UMD (33X as a causal variant) and the ClinVar database (with “pathogenic” 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 laboratory’s criteria to be classified as pathogenic. -

Gastric cancer;C3272841:Familial adenomatous polyposis 2 Pathogenic:1

Jun 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MUTYH-related disorder Pathogenic:1

Jul 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
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

Other links and lift over

dbSNP: rs587780751; hg19: chr1-45797835; COSMIC: COSV104641867; COSMIC: COSV104641867;