rs587781628

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePM2PP3_ModeratePP5_Very_Strong

The NM_001048174.2(MUTYH):c.1103-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000638 in 1,613,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 splice_acceptor

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 4.59

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.086845465 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.1, offset of 12, new splice context is: cctctcgggtctgctggcAGgac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 1-45331558-T-C is Pathogenic according to our data. Variant chr1-45331558-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45331558-T-C is described in Lovd as [Likely_pathogenic]. Variant chr1-45331558-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001048174.2 linkuse as main transcript	c.1103-2A>G		splice_acceptor_variant		ENST00000456914.7
MUTYH	NM_001128425.2 linkuse as main transcript	c.1187-2A>G		splice_acceptor_variant		ENST00000710952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000456914.7 linkuse as main transcript	c.1103-2A>G		splice_acceptor_variant		1	NM_001048174.2	A1	Q9UIF7-6
MUTYH	ENST00000710952.2 linkuse as main transcript	c.1187-2A>G		splice_acceptor_variant			NM_001128425.2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

249628

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135346

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000698

AC:

102

AN:

1461572

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000899

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000560

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	The c.1187-2A>G variant, also referred to as c.1145-2A>G and IVS12-2A>G, occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. Across three studies, this variant was reported in three colorectal cancer patients, including two patients who carried the variant in a compound heterozygous state with a second known pathogenic variant and in one patient who was heterozygous for the c.1187-2A>G variant (Wang et al. 2004; Eliason et al. 2005; Farrington et al. 2005). The variant was absent from 1845 control individuals but is reported at a frequency of 0.00003 in the European (Non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on only two alleles so it is presumed to be rare. RNA transcript analysis of RNA from one of the compound heterozygous patients revealed only the missense variant transcript and no wild type transcript, indicating that the splice acceptor variant is a null allele (Farrington et al. 2005). Based on the evidence and due to the potential impact of splice acceptor variants, the c.1187-2A>G variant is classified as likely pathogenic for MYH-associated polyposis. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change affects an acceptor splice site in intron 12 of the MUTYH gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 4 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs587781628, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with polyposis and/or colon/rectum cancer (PMID: 15236166, 15931596). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 9639A>G and IVS12-2A>G. ClinVar contains an entry for this variant (Variation ID: 141282). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 13 (Invitae). This variant disrupts a region of the MUTYH protein in which other variant(s) (p.Gly396Asp) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This variant causes an A to G nucleotide substitution at the -2 position of intron 12 of the MUTYH gene. This variant is also known as IVS12-2A>G and 9639A>G in the literature. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study has reported this variant to result in a null allele (PMID: 15931596). This variant has been reported in three individuals affected with colorectal cancer and/or polyposis, including two individuals who were compound heterozygous with a known pathogenic variant (PMID: 15236166, 15931596, 27145315). This variant has been identified in 7/281032 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 21, 2022	Variant summary: MUTYH c.1187-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 prime acceptor site. Four predict the variant creates/strengthens an exonic cryptic 3 prime acceptor site. One study reports experimental evidence in support of a deleterious effect of the variant, specifically demonstrating no expression of the variant allele following cDNA analysis in one patient (Farrington_2005). The variant allele was found at a frequency of 2.4e-05 in 249628 control chromosomes (gnomAD). c.1187-2A>G has been reported in the literature in individuals affected with MUTYH-associated Polyposis (e.g. Church_2016, Eliason_2005, Farrington_2005, Wang_2004). These data indicate that the variant is likely to be associated with disease. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic (n=8) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 31, 2019	The c.1187-2A>G variant has been reported in 2 individuals with colorectal cancer and/or polyps, one whom was compound heterozygous for this variant and a second pathogenic variant in MUTYH (Wang 2004, Eliason 2005). This variant has also been identified in 1/19908 East Asian chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org; dbSNP rs587781628). However, this frequency is low enough to be consistent with the frequency of MUTYH-related attenuated familial adenomatous polyposis in the general population. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets criteria to be classified as pathogenic for MUTYH-related attenuated familial adenomatous polyposis in an autosomal recessive manner based upon its predict impact to the protein. ACMG/AMP criteria applied: PVS1, PM3, PS4_P. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 29, 2019	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21171015, 26202870, 25525159, 19725997, 19245865, 27194394, 24444654, 27096365, 15635083, 15236166, 27799157, 29490034, 31277343, 30787465, 18534194, 27145315, 15931596) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 03, 2021	The MUTYH c.1187-2A>G variant (rs587781628), also known as IVS12-2A>G and 9639A>G, is reported in the literature in both the heterozygous and compound heterozygous states in individuals with MYH-associated polyposis (Church 2016, Eliason 2005, Farrington 2005, Wang 2004). This variant is also reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 141282). It is found in the general population with an overall allele frequency of 0.002% (7/281032 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice acceptor site of intron 12, and RNA analysis demonstrated transcripts with this splicing variant were absent, indicating this variant causes a null allele (Farrington 2005). Based on available information, this variant is considered to be pathogenic. REFERENCES Church J et al. The "Studded" Rectum: Phenotypic Evidence of MYH-Associated Polyposis. Dis Colon Rectum. 2016 Jun;59(6):565-9. PMID: 27145315. Eliason K et al. The potential for increased clinical sensitivity in genetic testing for polyposis colorectal cancer through the analysis of MYH mutations in North American patients. J Med Genet. 2005 Jan;42(1):95-6. PMID: 15635083. Farrington SM et al. Germline susceptibility to colorectal cancer due to base-excision repair gene defects. Am J Hum Genet. 2005 Jul;77(1):112-9. PMID: 15931596. Wang L et al. MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps. Gastroenterology. 2004 Jul;127(1):9-16. PMID: 15236166. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 20, 2017	This variant is located in a canonical splice-acceptor site and interferes with normal MUTYH mRNA splicing. In addition, this variant has been reported in individuals with colorectal cancer in the published literature (PMIDs: 15931596 (2005), 15635083 (2005), and 15236166 (2004)). A published RNA transcript analysis from a patient sample confirmed this variant causes loss of the wild-type transcript (PMID: 15931596 (2005)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 18, 2023	This variant causes an A to G nucleotide substitution at the -2 position of intron 12 of the MUTYH gene. This variant is also known as IVS12-2A>G and 9639A>G in the literature. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study has reported this variant to result in a null allele (PMID: 15931596). This variant has been reported in three individuals affected with colorectal cancer and/or polyposis, including two individuals who were compound heterozygous with a known pathogenic variant (PMID: 15236166, 15931596, 27145315). This variant has been identified in 7/281032 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	Sep 03, 2021	The c.1187-2A>G intronic pathogenic mutation results from an A to G substitution 2 nucleotides before coding exon 13 in the MUTYH gene. This alteration was reported in an individual who was diagnosed with colon cancer at age 38 and had 20-50 colon polyps, who also carried the well described MUTYH founder mutation p.G396D (also known as p.G382D) (Wang et al. Gastroenterology. 2004 Jul;127(1):9-16). In another study, this variant was reported in heterozygous form in a colon polyposis patient who previously tested negative for FAP and HNPCC (Eliason et al. J Med Genet. 2005 Jan;42(1):95-6). This variant has also been identified in the homozygous state and as compound heterozygous with MUTYH founder mutations in individuals with adenomatous polyposis (Ambry internal data). RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Note, this mutation is also referred to as c.1145-2A>G and IVS12-2A>G in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Carcinoma of colon

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Pathway Genomics

Oct 30, 2014

- -

Gastric cancer;C3272841:Familial adenomatous polyposis 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Uncertain

-0.050

Cadd

Pathogenic

Dann

Benign

0.92

Eigen

Pathogenic

0.82

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

1.0

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D

GERP RS

4.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.90

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.96

Position offset: -14

DS_AL_spliceai

1.0

Position offset: -2

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

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