rs876660190

chr1-45333100-C-CATCCAT

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM4 PP3 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 8.81

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 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	c.374_375insATGGAT	p.Trp124_Met125insIleTrp	inframe_insertion	5/16	ENST00000456914.7
MUTYH	NM_001128425.2	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	c.374_375insATGGAT	p.Trp124_Met125insIleTrp	inframe_insertion	5/16	1	NM_001048174.2	A1
MUTYH	ENST00000710952.2	c.458_459insATGGAT	p.Trp152_Met153insIleTrp	inframe_insertion	5/16		NM_001128425.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251484 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135916

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: 4 AN: 1461884 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

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.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:5

Likely pathogenic, no assertion criteria provided	clinical testing	Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	Aug 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
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	Revvity Omics, Revvity	Jun 13, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
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) -

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876660190; hg19: chr1-45798772;