rs2275602

Positions:

• chr1-45340208-G-A
• chr1-45340208-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_025077.4(TOE1):​c.-45G>A variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00207 in 1,613,756 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (55 hom.)
• Consequence: TOE1 NM_025077.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 4.27

Genes affected

TOE1 (HGNC:15954): (target of EGR1, exonuclease) Enables poly(A)-specific ribonuclease activity and snRNA binding activity. Involved in RNA phosphodiester bond hydrolysis, exonucleolytic and snRNA 3'-end processing. Located in Cajal body and cytoplasm. Implicated in pontocerebellar hypoplasia type 7. [provided by Alliance of Genome Resources, Apr 2022]

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 1-45340208-G-A is Benign according to our data. Variant chr1-45340208-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138310.We mark this variant Likely_benign, oryginal submissions are: {Benign=8, Uncertain_significance=1}. Variant chr1-45340208-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00224 (342/152374) while in subpopulation EAS AF= 0.0313 (162/5180). AF 95% confidence interval is 0.0273. There are 7 homozygotes in gnomad4. There are 218 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOE1	NM_025077.4	c.-45G>A		5_prime_UTR_variant	1/8	ENST00000372090.6	NP_079353.3
MUTYH	NM_001128425.2	c.36+11C>T		intron_variant		ENST00000710952.2	NP_001121897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOE1	ENST00000372090.6	c.-45G>A		5_prime_UTR_variant	1/8	1	NM_025077.4	ENSP00000361162	P1
MUTYH	ENST00000710952.2	c.36+11C>T		intron_variant			NM_001128425.2	ENSP00000518552

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 335 AN: 152256 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0312

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00677

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00337 AC: 840 AN: 249134 Hom.: 9 AF XY: 0.00336 AC XY: 454 AN XY: 135284

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0249

Gnomad SAS exome AF: 0.00252

Gnomad FIN exome AF: 0.00866

Gnomad NFE exome AF: 0.000900

Gnomad OTH exome AF: 0.00296

GnomAD4 exome AF: 0.00206 AC: 3006 AN: 1461382 Hom.: 55 Cov.: 33 AF XY: 0.00210 AC XY: 1527 AN XY: 727016

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0397

Gnomad4 SAS exome AF: 0.00266

Gnomad4 FIN exome AF: 0.00832

Gnomad4 NFE exome AF: 0.000514

Gnomad4 OTH exome AF: 0.00253

GnomAD4 genome AF: 0.00224 AC: 342 AN: 152374 Hom.: 7 Cov.: 32 AF XY: 0.00293 AC XY: 218 AN XY: 74520

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0313

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00677

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.00198

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Familial adenomatous polyposis 2 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 27, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 17, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 03, 2016	- -

Carcinoma of colon Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MUTYH c.36+11C>T variant was identified in 7 of 276 proband chromosomes (frequency: 0.04) from individuals or families with (Shinmura 2014,Tao 2004, Zhou 2005). The variant was also identified in dbSNP (ID: rs2275602) as "With other allele", in ClinVar (3x as Benign by GeneDx, Colour Genomics and Prevention Genetics), Insight Colon Cancer Gene Variant Database (4x), and in UMD-LSDB (2x as unclassified variant). The variant was also identified by our laboratory in 7 individuals including 6 with a clinical indication for hereditary colon cancer testing. The variant was not identified in GeneInsight-COGR, Cosmic, or MutDB databases. The variant was identified in control databases in 914 of 275438 chromosomes (11 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 23810 chromosomes (freq: 0.00008), Other in 17 of 6424 chromosomes (freq: 0.003), Latino in 3 of 34366 chromosomes (freq: 0.00009), European Non-Finnish in 133 of 125622 chromosomes (freq: 0.001), East Asian in 467 of 18808 chromosomes (freq: 0.02), Finnish in 213 of 25526 chromosomes (freq: 0.008), and South Asian in 79 of 30766 chromosomes (freq: 0.003), while the variant was not observed in the Ashkenazi Jewish population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing; however, the c.36+11C>T variant is located in the boundary region between MUTYH exon 1 and intron 1 and many reports have suggested that gene variants in the neighborhood of the junction are often accompanied by abnormal splicing (Tao 2008). In a Japanese population-based study, a statistically significant association was demonstrated between this variant and increased CRC risk (Tao 2008). Moreover, one haplotype containing the variant c.36+11T was demonstrated to be associated with increased CRC risk (OR of 1.43, haplotype .36+11C>T, c.504+35A>G, c.934−2A>G, and c.1014G>C, “TGAC”). The c.36+11C>T variant was found to be in complete linkage disequilibrium with two other MUTYH variants, –280G>A and c.1389G>C. These results indicate that individuals with the MUTYH – 280A/c.36+11T/c.1431C genotypes or the TGAC haplotype are susceptible to CRC (Tao 2008). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

Pontocerebellar hypoplasia type 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2275602; hg19: chr1-45805880; COSMIC: COSV59156766; COSMIC: COSV59156766;