1-45333171-C-T

Position:

• chr1-45333171-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001048174.2(MUTYH):​c.305-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,894 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MUTYH NM_001048174.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• 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]

ENSG00000288208 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.046615582 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.7, offset of 12, new splice context is: tcccccaatgtgggtctcAGagg. 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
• PP5: Variant 1-45333171-C-T is Pathogenic according to our data. Variant chr1-45333171-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 186819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45333171-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.305-1G>A		splice_acceptor_variant, intron_variant		ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.305-1G>A		splice_acceptor_variant, intron_variant		1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.893-1G>A		splice_acceptor_variant, intron_variant				ENSP00000499896.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461894 Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000239 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jul 24, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 06, 2024	This variant causes a G>A nucleotide substitution at the canonical -1 position of intron 4 splice acceptor of the MUTYH gene. This is also know as IVS4-1G>A and c.347-1G>A based on an alternative MUTYH transcript (NM_001048171). Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed by published RNA studies, this variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with adenomatous polyposis and/or colorectal cancer together with another known pathogenic variant in the same gene (PMID: 12853198, 19732775, 24470512; communication with an external laboratory, ClinVar SCV000545764.5; Color internal data). Compound heterozygosity consistent with autosomal recessive inheritance has been reported in three of these probands (PMID: 12853198, 19732775, 24470512). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Feb 06, 2024	The MUTYH c.389-1G>A intronic change results in a G to A substitution at the -1 position of intron 4 of the MUTYH gene. This variant is predicted to result in aberrant splicing. This variant has been reported in conjunction with another pathogenic variant in individuals with adenomas (PMID: 19732775, 24470512). This variant is also absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 14, 2023	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 individuals with colorectal cancer and multiple polyposis (PMID: 12853198, 19032956, 19732775, 24470512). This variant is also known as c.347-1G>A. ClinVar contains an entry for this variant (Variation ID: 186819). 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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 28, 2021	The c.389-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 5 in the MUTYH gene. This nucleotide position is highly conserved in available vertebrate species. 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This pathogenic mutation has been identified in conjunction with a MUTYH founder mutation in at least two individuals with polyposis (Sampson JR et al. Lancet 2003 Jul;362:39-41; Vogt S et al. Gastroenterology 2009 Dec;137(6):1976-85.e1-10; Guarinos C et al. Clin Cancer Res 2014 Mar;20(5):1158-68). Of note, this mutation is also designated as 347-1G>A 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	Apr 26, 2023	This variant causes a G>A nucleotide substitution at the canonical -1 position of intron 4 splice acceptor of the MUTYH gene. This is also know as IVS4-1G>A and c.347-1G>A based on an alternative MUTYH transcript (NM_001048171). Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed by published RNA studies, this variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with adenomatous polyposis and/or colorectal cancer together with another known pathogenic variant in the same gene (PMID: 12853198, 19732775, 24470512; communication with an external laboratory, ClinVar SCV000545764.5; Color internal data). Compound heterozygosity consistent with autosomal recessive inheritance has been reported in three of these probands (PMID: 12853198, 19732775, 24470512). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The MUTYH, c.389-1G>A variant was identified in 8 of 3318 proband chromosomes (frequency: 0.002) from individuals or families with colorectal adenomatous polyposis in the German, UK, Dutch and Spanish populations (Guarinos 2014, Nielsen 2009, Vogt 2009, Sampson 2003, Filipe 2009). The variant was identified in dbSNP (ID: rs372267274) as “With Pathogenic allele.” In the NHLBI Exome Sequencing Project, the variant was identified in 1 of 8600 European Americans and was not identified in African Americans. The variant was listed in the ClinVar database as Pathogenic by Ambry Genetics and was reported 4x in InSiGHT Colon Cancer Gene Variant Database (LOVD). Additionally, the variant was found to occur in biallelic mode with the pathogenic variant c.536A>G in a patient with 14 polyps but no colorectal cancer (Sampson 2003). The variant was identified in 2 patients with attenuated FAP in trans with the pathogenic variant c.1187G>A (Filipe 2009). The c.389-1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. 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 meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.5

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		0.70		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;