1-45333415-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001048174.2(MUTYH):c.262C>G(p.Arg88Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R88W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense, splice_region

Scores

Splicing: ADA: 0.02090

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.40

Publications

12 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 2 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 56 uncertain in NM_001048174.2

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12842497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.262C>G	p.Arg88Gly	missense_variant, splice_region_variant	Exon 3 of 16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7 link	c.262C>G	p.Arg88Gly	missense_variant, splice_region_variant	Exon 3 of 16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.850C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

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:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111962

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Dec 05, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R116G variant (also known as c.346C>G), located in coding exon 3 of the MUTYH gene, results from a C to G substitution at nucleotide position 346. The arginine at codon 116 is replaced by glycine, an amino acid with dissimilar properties. This nucleotide position is not well conserved in available vertebrate species. This amino acid position is not well 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, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Jun 01, 2021

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with glycine at codon 116 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Familial adenomatous polyposis 2

Uncertain:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 116 of the MUTYH protein (p.Arg116Gly). 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: 823807). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.087

.;.;.;.;.;T;.;.;.;T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.95

.;D;.;D;D;D;D;D;D;D;D;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.087

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

.;.;.;.;.;L;.;.;.;.;.;.

PhyloP100

2.4

PrimateAI

Benign

0.23

PROVEAN

Benign

-2.3

N;N;N;N;N;N;N;N;N;D;N;N

REVEL

Benign

0.056

Sift

Benign

0.34

T;T;T;T;T;T;T;T;T;T;T;D

Sift4G

Benign

0.40

T;T;T;T;T;T;T;T;T;T;T;D

Polyphen

0.072, 0.10, 0.063

.;.;.;.;.;B;B;.;B;.;.;.

Vest4

0.28

MutPred

0.46

.;.;.;.;.;.;.;.;Loss of stability (P = 0.0527);.;.;.;

MVP

0.49

MPC

0.18

ClinPred

0.076

GERP RS

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.44

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.021

dbscSNV1_RF

Benign

0.074

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

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