rs786202442

chr1-45331745-TGG-Tchr1-45331745-T-TGchr1-45331745-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001048174.2(MUTYH):c.1016_1017del(p.Pro339GlnfsTer164) variant causes a frameshift change. Variant has been reported in ClinVar as Likely 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)
• Consequence: MUTYH NM_001048174.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.49

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-45331745-TGG-T is Pathogenic according to our data. Variant chr1-45331745-TGG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406858.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.1016_1017del	p.Pro339GlnfsTer164	frameshift_variant	12/16	ENST00000456914.7
MUTYH	NM_001128425.2	c.1100_1101del	p.Pro367GlnfsTer164	frameshift_variant	12/16	ENST00000710952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000456914.7	c.1016_1017del	p.Pro339GlnfsTer164	frameshift_variant	12/16	1	NM_001048174.2	A1
MUTYH	ENST00000710952.2	c.1100_1101del	p.Pro367GlnfsTer164	frameshift_variant	12/16		NM_001128425.2

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 27, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2020	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. This variant disrupts the p.Glu480 and p.Val493 amino acid residues in MUTYH. Other variants that disrupt these residues have been determined to be pathogenic (PMID: 14999774, 15635083, 12707038, 16557584, 17949294, 17931073). This suggests that these residues are clinically significant, and that variants that disrupt these residues are likely to be disease-causing. This variant has not been reported in the literature in individuals with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 406858). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the MUTYH gene (p.Pro367Glnfs*164). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 183 amino acids of the MUTYH protein. -

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: rs768130289; hg19: chr1-45797417;