rs372267274

chr1-45333171-C-Gchr1-45333171-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_001048174.2(MUTYH):c.305-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MUTYH NM_001048174.2 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 7.46

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 16 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.046615582 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.1, offset of 12, new splice context is: tcccccactgtgggtctcAGagg. 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, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-45333171-C-G is Pathogenic according to our data. Variant chr1-45333171-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 234229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45333171-C-G is described in Lovd as [Likely_pathogenic]. Variant chr1-45333171-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001048174.2	c.305-1G>C		splice_acceptor_variant		ENST00000456914.7
MUTYH	NM_001128425.2	c.389-1G>C		splice_acceptor_variant		ENST00000710952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000456914.7	c.305-1G>C		splice_acceptor_variant		1	NM_001048174.2	A1
MUTYH	ENST00000710952.2	c.389-1G>C		splice_acceptor_variant			NM_001128425.2

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000478

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461894 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

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: 0.000478

Alfa AF: 0.0000478 Hom.: 0

Bravo AF: 0.0000680

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change affects an acceptor splice site in intron 4 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with colorectal polyposis (PMID: 15366000, 17949294, 23561487; Invitae). 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 c.347-1G>C. ClinVar contains an entry for this variant (Variation ID: 234229). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 5 (Invitae). This variant disrupts a region of the MUTYH protein in which other variant(s) (p.Trp131Arg) have been determined to be pathogenic (PMID: 12853198, 19032956, 19394335, 19732775, 25820570, 26681312; 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	Baylor Genetics	Sep 29, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Aug 09, 2019	The c.389-1G>C variant is predicted to lead to either nonsense-mediated mRNA decay or an abnormal protein product by destroying a canonical splice acceptor site. Loss-of-function variants in MUTYH are known to be pathogenic (Ali 2008, Nielsen 2011). The c.389-1G>C variant is not present in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). This variant has been reported in multiple individuals with MAP who are either homozygous or compound heterozygous for a second MUTYH pathogenic variant (Isidro 2004, Olschwang 2007, Torrezan 2013). Thus, this variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	This variant causes a G to C nucleotide substitution at the -1 position of intron 4 splice acceptor site of the MUTYH gene. This variant is also known as c.347-1G>C based on the NM_001048171.1 transcript. Although RNA studies have not been reported, this variant is expected to disrupt RNA splicing and result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with adenomatous polyposis in compound heterozygous state with pathogenic mutations (PMID: 12853198, 15366000, 17949294, 19032956, 19732775, 19793053, 23561487). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice acceptor site, c.389-1G>A and c.389-2A>G, are known to be disease-causing (Clinvar variation ID: 186819 and 215998). 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	Oct 28, 2016	Variant summary: The MUTYH c.389-1G>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant abolishes the 3' splicing acceptor site in intron 4. This variant is absent in 121386 control chromosomes, however, has been reported in numerous MAP patients. 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	Mendelics	Jul 02, 2018	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jan 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 24, 2021	The c.389-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 5 of the MUTYH gene. This alteration has been identified as homozygous and in conjunction with other common pathogenic MUTYH mutations in multiple patients with 30-100 colorectal adenomas (Isidro G et al. Hum. Mutat. 2004 Oct;24:353-4; Torrezan GT et al. Orphanet J Rare Dis. 2013 Apr;8:54; Filipe B et al. Clin. Genet. 2009 Sep;76:242-55; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Of note, this alteration is also designated c.347-1G>C in published literature. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 01, 2023	This variant causes a G to C nucleotide substitution at the -1 position of intron 4 splice acceptor site of the MUTYH gene. This variant is also known as c.347-1G>C based on the NM_001048171.1 transcript. Although RNA studies have not been reported, this variant is expected to disrupt RNA splicing and result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with adenomatous polyposis in compound heterozygous state with pathogenic mutations (PMID: 12853198, 15366000, 17949294, 19032956, 19732775, 19793053, 23561487). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice acceptor site, c.389-1G>A and c.389-2A>G, are known to be disease-causing (Clinvar variation ID: 186819 and 215998). 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 19, 2023	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; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 19725997, 19732775, 17949294, 12853198, 24470512, 15366000, 23561487, 19793053, 19032956, 33084842, 35264596, 33606809) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 07, 2017	- -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The c.389-1G>C variant was identified in 3 of 152 proband chromosomes (frequency: 0.020) from Portuguese and Brazilian individuals or families with MAP/AFAP/FAP (Isidro 2004, Torrezan 2013); however, control chromosomes were not evaluated in these studies. The c.389-1G>C variant was not identified in dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), database MutDB, “Zhejiang Colon Cancer Database”, the ClinVar database, GeneInsight VariantWire database, and COSMIC. The variant was identified in UMD (12x as a Causal variant), with co-occurring pathogenic MUTYH variants (including: c.494A>G and c.1145G>A). The c.389-1G>C variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence and this variant is the type of which could be expected to cause the disorder. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant is classified as pathogenic. -

Neoplasm of stomach;C0206711:Pilomatrixoma;C3272841:Familial adenomatous polyposis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	35
Dann	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.78		Position offset: -13
DS_AL_spliceai		0.98		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs372267274; hg19: chr1-45798843;