rs761468459

Positions:

Variant summary

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

The ENST00000456914.7(MUTYH):c.775del(p.Ala259ProfsTer32) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,138 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A259A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MUTYH
ENST00000456914.7 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 7.55

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:

Genome browser will be placed here

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 1-45332239-GC-G is Pathogenic according to our data. Variant chr1-45332239-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45332239-GC-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2 linkuse as main transcript	c.859del	p.Ala287ProfsTer32	frameshift_variant	10/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2 linkuse as main transcript	c.775del	p.Ala259ProfsTer32	frameshift_variant	10/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2 linkuse as main transcript	c.859del	p.Ala287ProfsTer32	frameshift_variant	10/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7 linkuse as main transcript	c.775del	p.Ala259ProfsTer32	frameshift_variant	10/16	1	NM_001048174.2	ENSP00000407590	A1	Q9UIF7-6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250896

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135738

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727206

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Jun 15, 2023	ACMG criteria used to clasify this variant:PVS1, PS4_SUP, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 433934). This variant is also known as c.817delG, p.A273PfsX32. This premature translational stop signal has been observed in individual(s) with polyposis (PMID: 16557584). This variant is present in population databases (rs761468459, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Ala287Profs*32) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 29, 2024	This variant deletes 1 nucleotide in exon 10 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant (also known as c.817del in the literature) has been reported in an individual affected with MUTYH-associated polyposis (PMID: 16557584). This variant has also been identified in 1/250896 chromosomes 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	Baylor Genetics	Oct 14, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 06, 2018	The p.Ala287ProfsX32 variant in MUTYH has been reported in the heterozygous stat e in one individuals with familial adenomatouspolyposis (Aretz 20016). It has al so been identified in 1/30782 of South Asian chromosomes by gnomAD (http://gnoma d.broadinstitute.org). This variant is predicted to cause a frameshift, which al ters the protein?s amino acid sequence beginning at position 287 and leads to a premature termination codon 32 amino acids downstream. This alteration is then p redicted to lead to a truncated or absent protein. In summary, although addition al studies are required to fully establish its clinical significance, the p.Ala2 87ProfsX32 variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 02, 2023	The c.859delG variant, located in coding exon 10 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 859, causing a translational frameshift with a predicted alternate stop codon (p.A287Pfs*32). This variant (designated as MUTYH c.817delG p.A273PfsX32) has been reported in the heterozygous state in one individual with a clinical diagnosis of familial adenomatous polyposis (Aretz S et al. Int. J. Cancer. 2006 Aug;119:807-14). In addition to the clinical data presented in the literature, 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. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Feb 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 15, 2020	This variant deletes 1 nucleotide in exon 10 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant (also known as c.817del in the literature) has been reported in an individual affected with MUTYH-associated polyposis (PMID: 16557584). This variant has also been identified in 1/250896 chromosomes 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. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in the heterozygous state in an individual with a history of polyposis (PMID: 16557584); Also known as 817delG; This variant is associated with the following publications: (PMID: 16557584) -

Carcinoma of colon

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MUTYH p.Ala287ProfsX32 variant was identified in 1 of 658 proband chromosomes (frequency: 0.002) from individuals or families with MUTYH associated polyposis, and was not identified in 116 control chromosomes from healthy individuals (Aretz 2006). The p.Ala287ProfsX32 variant was also identified in HGMD and the â€šÃ„ÃºInSiGHT Colon Cancer Databaseâ€šÃ„Ã¹. The p.Ala287ProfsX32 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 287 and leads to a premature stop codon 32 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants in the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

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

Other links and lift over