Variant chr1-45333100-C-CATCCAT details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM4PP3PP5_Very_Strong

The NM_001048174.2(MUTYH):c.374_375insATGGAT(p.Trp124_Met125insIleTrp) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 8.81

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001048174.2.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 1-45333100-C-CATCCAT is Pathogenic according to our data. Variant chr1-45333100-C-CATCCAT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 233094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001048174.2 linkuse as main transcript	c.374_375insATGGAT	p.Trp124_Met125insIleTrp	inframe_insertion	5/16	ENST00000456914.7
MUTYH	NM_001128425.2 linkuse as main transcript	c.458_459insATGGAT	p.Trp152_Met153insIleTrp	inframe_insertion	5/16	ENST00000710952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000456914.7 linkuse as main transcript	c.374_375insATGGAT	p.Trp124_Met125insIleTrp	inframe_insertion	5/16	1	NM_001048174.2	A1	Q9UIF7-6
MUTYH	ENST00000710952.2 linkuse as main transcript	c.458_459insATGGAT	p.Trp152_Met153insIleTrp	inframe_insertion	5/16		NM_001128425.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251484

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Feb 02, 2023	ACMG criteria used to clasify this variant: PS3_MOD, PS4_MOD, PM4, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	Aug 09, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This variant, c.453_458dup, results in the insertion of 2 amino acid(s) of the MUTYH protein (p.Trp152_Met153insIleTrp), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has been observed in individuals with MUTYH-associated polyposis (PMID: 12606733, 16557584, 26446593). This variant is also known as 137insIW, p.137insIleTrp, c.411_416dupATGGAT and 411dupATGGAT. ClinVar contains an entry for this variant (Variation ID: 233094). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MUTYH function (PMID: 19953527, 20418187). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 13, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	Aug 07, 2021	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2023	In-frame insertion of two amino acids in a non-repeat region; Published functional studies demonstrate weaker localization to the nucleus, reduced DNA glycosylase activity, and higher levels of DNA 8-oxodG accumulation compared to wild type (D'Agostino et al., 2010; Molatore et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.411_416dupATGGAT or 137insIW; This variant is associated with the following publications: (PMID: 19953527, 16287072, 14633673, 12606733, 17161978, 16557584, 26446593, 19725997, 20418187) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 16, 2022	This variant causes a duplication of 6 nucleotides in exon 5 of the MUTYH gene, resulting in in-frame insertion of isoleucine and tryptophan between codons 152 and 153 in the MUTYH protein. This variant is also known as 137insIW, p.137insIleTrp, p.W138_M139insIW, c.411_416dupATGGAT and 411dupATGGAT. Functional studies have shown that this in-frame insertion results in reduced substrate binding and impaired glycosylase activity (PMID: 19953527, 20418187). This variant has been reported in homozygosity or in compound heterozygosity in multiple individuals affected with MUTYH-associated polyposis (PMID: 12606733, 16287072, 16557584, 26446593). This variant has been identified in 1/251484 chromosomes 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	Ambry Genetics	Dec 22, 2022	The c.453_458dupATGGAT variant (also known as p.W152_M153insIW), located in coding exon 5 of the MUTYH gene, results from an in-frame duplication of 6 nucleotides at positions 453 to 458. This results in the insertion of an extra isoleucine and tryptophan residue between codons 152 and 153. This alteration has been detected in trans with a pathogenic MUTYH mutation in a 38-year-old male diagnosed with polyposis, colorectal cancer, and duodenal adenomas, as well as in the homozygous state in a 40-year-old male diagnosed with attenuated polyposis (Sieber OM et al. N Engl J Med. 2003 Feb 27;348(9):791-9; Russell AM et al. Int J Cancer. 2006 Apr 15;118(8):1937-40; Aretz S et al. Int J Cancer. 2006 Aug 15;119(4):807-14). This alteration has also been identified in conjunction with a pathogenic MUTYH mutation in an individual with adenomatous polyposis; however, the phase (whether in cis or trans) was not determined (Ambry internal data). Binding affinity and glycosylase activity assays showed this alteration caused a reduction in activity (Molatore S et al. Hum Mutat. 2010 Feb;31(2):159-66; D'Agostino VG et al. DNA Repair (Amst). 2010 Jun 4;9(6):700-7). Of note, this alteration is designated as 137insIW in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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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