Genetic Variant MUTYH:p.Arg340GlyfsTer40 (chr1-45331745-TG-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

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

The NM_001048174.2(MUTYH):c.1017delC(p.Arg340GlyfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P339P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.280

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:

ENSG00000288208 (HGNC:):

ENSG00000288208 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 1-45331745-TG-T is Pathogenic according to our data. Variant chr1-45331745-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 491999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45331745-TG-T is described in Lovd as [Likely_pathogenic]. Variant chr1-45331745-TG-T is described in Lovd as [Likely_pathogenic]. Variant chr1-45331745-TG-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.1017delC	p.Arg340GlyfsTer40	frameshift_variant	Exon 12 of 16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7 link	c.1017delC	p.Arg340GlyfsTer40	frameshift_variant	Exon 12 of 16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.1605delC		non_coding_transcript_exon_variant	Exon 16 of 21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250124

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135574

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:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727200

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:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:2

Mar 09, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 1 nucleotide in exon 12 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 has been reported in individuals affected with MUTYH-associated polyposis and/or colorectal cancer (PMID: 18515411, 19032956, 19732775, 20687945). In one of these affected individuals, this variant has been determined to be compound heterozygous with another pathogenic variant in the same gene (PMID: 19732775), indicating that this variant contributes to MUTYH-associated polyposis in an autosomal recessive manner. This variant has been identified in 1/250124 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. -

Jul 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg368Glyfs*40) 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). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with MUTYH-associated polyposis (PMID: 18515411, 19732775). This variant is also known as c.1092delC. ClinVar contains an entry for this variant (Variation ID: 491999). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Sep 15, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1101delC pathogenic mutation, located in coding exon 12 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 1101, causing a translational frameshift with a predicted alternate stop codon (p.R368Gfs*40). This alteration has been previously identified in conjunction with another pathogenic MUTYH mutation in 2 unrelated individuals with colorectal adenomas and/or colorectal cancer (Dallosso AR et al. Gut, 2008 Sep;57:1252-5; Vogt S et al. Gastroenterology, 2009 Dec;137:1976-85.e1-10). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Feb 01, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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