1-45332763-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_001128425.2(MUTYH):c.576G>T(p.Lys192Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K192E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MUTYH
NM_001128425.2 missense, splice_region

Scores

Splicing: ADA: 0.9996

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.25

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

familial adenomatous polyposis 2
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
colorectal cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
familial ovarian cancer
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

MUTYH links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 58 uncertain in NM_001128425.2

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001128425.2 link	c.576G>T	p.Lys192Asn	missense_variant, splice_region_variant	Exon 7 of 16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2 link	c.492G>T	p.Lys164Asn	missense_variant, splice_region_variant	Exon 7 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MUTYH	ENST00000710952.2 link	c.576G>T	p.Lys192Asn	missense_variant, splice_region_variant	Exon 7 of 16		NM_001128425.2	ENSP00000518552.2
MUTYH	ENST00000456914.7 link	c.492G>T	p.Lys164Asn	missense_variant, splice_region_variant	Exon 7 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1 link	n.1080G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 11 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Uncertain:1

Nov 08, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This sequence change replaces lysine with asparagine at codon 192 of the MUTYH protein (p.Lys192Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. It also falls at the last nucleotide of exon 7 of the MUTYH coding sequence. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MUTYH-related disease. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Aug 12, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.K192N variant (also known as c.576G>T), located in coding exon 7 of the MUTYH gene, results from a G to T substitution at nucleotide position 576. The amino acid change results in lysine to asparagine at codon 192, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 7, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive; however, direct evidence is insufficient at this time (Ambry internal data). In addition, as a missense substitution this is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.55

.;T

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

0.84

PhyloP100

5.2

PROVEAN

Pathogenic

-6.1

D;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.84

MutPred

0.75

Loss of disorder (P = 0.0345);Loss of disorder (P = 0.0345);

MVP

0.89

ClinPred

0.99

GERP RS

5.3

PromoterAI

-0.074

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.93

Mutation Taster

=4/96

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.28

Position offset: -19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over