chr1-45333166-C-T

Position:

• chr1-45333166-C-T

Variant summary

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

The NM_001048174.2(MUTYH):​c.309G>A​(p.Trp103Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUTYH NM_001048174.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.75

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 1-45333166-C-T is Pathogenic according to our data. Variant chr1-45333166-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.393G>A	p.Trp131Ter	stop_gained	5/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.309G>A	p.Trp103Ter	stop_gained	5/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.393G>A	p.Trp131Ter	stop_gained	5/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.309G>A	p.Trp103Ter	stop_gained	5/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	This variant changes 1 nucleotide in exon 5 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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	curation	Sema4, Sema4	Mar 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 10, 2024	The p.W131* pathogenic mutation (also known as c.393G>A), located in coding exon 5 of the MUTYH gene, results from a G to A substitution at nucleotide position 393. This changes the amino acid from a tryptophan to a stop codon within coding exon 5. This pathogenic mutation was identified in a proband who underwent hereditary cancer multigene panel testing (LaDuca H et al. Genet. Med. 2014 Nov;16:830-7; LaDuca H et al. PLoS ONE 2017 Feb;12:e0170843). 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. -

Familial adenomatous polyposis 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 09, 2023	This sequence change creates a premature translational stop signal (p.Trp131*) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 140811). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 15, 2017	Variant summary: The MUTYH c.393G>A (p.Trp131X) variant is a nonsense change that results in the loss of the ~419 amino acids of MUTYH protein (~75%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.508delG, p.Val170X; c.1147delC, p.Ala385fsX23; c.1227_1228dupGG, p.Glu410fsX43). One in silico tool predicts a damaging outcome for this variant. The variant is absent from the large control population datasets of ExAC and gnomAD (~25184 and 246196 chrs tested, respectively). This variant has been reported in at least one affected individuals via a published report (LaDuca_2014). In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2017

This pathogenic variant is denoted MUTYH c.393G>A at the cDNA level and p.Trp131Ter (W131X) atthe protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon(TGG>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one individual referred for clinical testing for inheritedcancer (LaDuca 2014). We consider it to be pathogenic -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;D;D;D;D
Vest4		0.97
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs587781295; hg19: chr1-45798838; COSMIC: COSV105235975; COSMIC: COSV105235975;