rs1553129638

Positions:

• chr1-45333137-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000456914.7(MUTYH):​c.337del​(p.Gln113ArgfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUTYH ENST00000456914.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.46

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 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 1-45333137-TG-T is Pathogenic according to our data. Variant chr1-45333137-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 464719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45333137-TG-T is described in Lovd as [Likely_pathogenic]. Variant chr1-45333137-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.421del	p.Gln141ArgfsTer5	frameshift_variant	5/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.337del	p.Gln113ArgfsTer5	frameshift_variant	5/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.421del	p.Gln141ArgfsTer5	frameshift_variant	5/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.337del	p.Gln113ArgfsTer5	frameshift_variant	5/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 26, 2017	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MUTYH are known to be pathogenic. This particular variant has been reported as compound heterozygous with other pathogenic variants in MUTYH in individuals with Muir–Torre syndrome (PMID: 16207212), attenuated polyposis (PMID: 22865608), and colorectal adenomas (PMID: 22773231). This variant is also known as 379delC. This sequence change deletes 1 nucleotide in exon 5 of the MUTYH mRNA (c.421delC), causing a frameshift at codon 141. This creates a premature translational stop signal (p.Gln141Argfs*5) and is expected to result in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1553129638; hg19: chr1-45798809;