rs587781338

Variant summary

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

The NM_001048174.2(MUTYH):​c.856C>T​(p.Gln286Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,461,892 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. Q286Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 stop_gained

Scores

1
6

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: -0.790
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]

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 1-45332080-G-A is Pathogenic according to our data. Variant chr1-45332080-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 140876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45332080-G-A is described in Lovd as [Pathogenic]. Variant chr1-45332080-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MUTYHNM_001128425.2 linkuse as main transcriptc.940C>T p.Gln314Ter stop_gained 11/16 ENST00000710952.2
MUTYHNM_001048174.2 linkuse as main transcriptc.856C>T p.Gln286Ter stop_gained 11/16 ENST00000456914.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MUTYHENST00000710952.2 linkuse as main transcriptc.940C>T p.Gln314Ter stop_gained 11/16 NM_001128425.2
MUTYHENST00000456914.7 linkuse as main transcriptc.856C>T p.Gln286Ter stop_gained 11/161 NM_001048174.2 A1Q9UIF7-6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251468
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135918
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:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1461892
Hom.:
0
Cov.:
36
AF XY:
0.0000193
AC XY:
14
AN XY:
727248
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:
0.0000243
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 06, 2024This sequence change creates a premature translational stop signal (p.Gln314*) 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 (rs587781338, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with a personal and family history of prostate cancer and MUTYH-associated polyposis (PMID: 15635083, 24556621). This variant is also known as Y165C. ClinVar contains an entry for this variant (Variation ID: 140876). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsApr 16, 2023- -
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJan 05, 2024The p.Q314* pathogenic mutation (also known as c.940C>T), located in exon 11 of the MUTYH gene, results from a C to T substitution at nucleotide position 940. This changes the amino acid from a glutamine to a stop codon within exon 11. This mutation has been reported in an individual with polyposis who also harbored the MUTYH p.Y179C mutation (Eliason K et al. J. Med. Genet. 2005 Jan;42(1):95-6). This mutation has also been reported in the heterozygous state in familial prostate cancer (Leongamornlert D et al. Br. J. Cancer 2014 Mar;110(6):1663-72). 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. -
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 15, 2020This variant changes 1 nucleotide in exon 11 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 been identified in 3/251468 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:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 05, 2024Nonsense 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); Also known as Q300X; This variant is associated with the following publications: (PMID: 17949294, 25525159, 19725997, 37319387, 24556621, 26556299, 30787465, Sadaps2019[Abstract], 34761457, 15635083) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.021
T
BayesDel_noAF
Benign
-0.14
CADD
Pathogenic
29
DANN
Benign
0.93
Eigen
Benign
-0.19
Eigen_PC
Benign
-0.54
FATHMM_MKL
Benign
0.15
N
MutationTaster
Benign
1.0
A;A;A;A;A;A;A;A;A;A;N;N;N;N
Vest4
0.72
GERP RS
-0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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.

Other links and lift over

dbSNP: rs587781338; hg19: chr1-45797752; API