Variant rs1553125075 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001048174.2(MUTYH):c.1318_1319del(p.Thr440ArgfsTer63) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T440T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

MUTYH
NM_001048174.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 0.130

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-45331254-GGT-G is Pathogenic according to our data. Variant chr1-45331254-GGT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 486917.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.1318_1319del	p.Thr440ArgfsTer63	frameshift_variant	14/16	ENST00000456914.7
MUTYH	NM_001128425.2 linkuse as main transcript	c.1402_1403del	p.Thr468ArgfsTer63	frameshift_variant	14/16	ENST00000710952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000456914.7 linkuse as main transcript	c.1318_1319del	p.Thr440ArgfsTer63	frameshift_variant	14/16	1	NM_001048174.2	A1	Q9UIF7-6
MUTYH	ENST00000710952.2 linkuse as main transcript	c.1402_1403del	p.Thr468ArgfsTer63	frameshift_variant	14/16		NM_001128425.2

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This variant changes 2 nucleotides in exon 14 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 04, 2023	This sequence change creates a premature translational stop signal (p.Thr468Argfs*63) in the MUTYH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 82 amino acid(s) of the MUTYH protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is also known as Gln512-Phe519. ClinVar contains an entry for this variant (Variation ID: 486917). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the conserved PCNA binding motif of the MUTYH protein, which has been shown to be critical for MUTYH-PCNA binding and repair efficiency (PMID: 11092888, 26377631, 11433026, 11864576). While functional studies have not been performed to directly test the effect of this variant on MUTYH protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 01, 2023	This variant changes 2 nucleotides in exon 14 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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	Ambry Genetics	Sep 08, 2022	The c.1402_1403delAC pathogenic mutation, located in coding exon 14 of the MUTYH gene, results from a deletion of two nucleotides at nucleotide positions 1402 to 1403, causing a translational frameshift with a predicted alternate stop codon (p.T468Rfs*63). This truncating mutation was seen twice in conjunction with a second MUTYH pathogenic mutation (phase unknown) in two individuals with features of MUTYH-associated polyposis (MAP) (Ambry internal data). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing