chr1-45333448-C-T

Position:

chr1-45333448-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_001048174.2(MUTYH):c.229G>A(p.Asp77Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,096 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D77G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:1

Conservation

PhyloP100: 3.47

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_001048174.2

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2 linkuse as main transcript	c.313G>A	p.Asp105Asn	missense_variant	3/16	ENST00000710952.2
MUTYH	NM_001048174.2 linkuse as main transcript	c.229G>A	p.Asp77Asn	missense_variant	3/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2 linkuse as main transcript	c.313G>A	p.Asp105Asn	missense_variant	3/16		NM_001128425.2
MUTYH	ENST00000456914.7 linkuse as main transcript	c.229G>A	p.Asp77Asn	missense_variant	3/16	1	NM_001048174.2	A1	Q9UIF7-6

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251488

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135920

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:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727242

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000889

Hom.:

Bravo

AF:

0.0000264

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2022	Published functional studies demonstrate no damaging effect (Komine et al., 2015; Shinmura et al., 2016); Observed in individuals with a personal or family history of colorectal cancer and/or polyps (Nielsen et al., 2005; Niessen et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(Asp91Asn); This variant is associated with the following publications: (PMID: 16408224, 16140997, 25820570, 26694661) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 02, 2017	- -

Familial adenomatous polyposis 2

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces aspartic acid with asparagine at codon 105 of the MUTYH protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant protein (also known as p.Asp77Asn and p.Asp91Asn in the literature) exhibits similar DNA glycosylase activity and ability in mutation suppression compared to the wild-type protein (PMID: 25820570, 26694661). This variant has been detected in heterozygosity without a known second mutation in at least one individual affected with colorectal cancer and polyposis (PMID: 16140997, 16408224). This variant has also been identified in 9/282862 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 105 of the MUTYH protein (p.Asp105Asn). This variant is present in population databases (rs587780746, gnomAD 0.007%). This missense change has been observed in individual(s) with sporadic colorectal cancer (PMID: 16140997, 16408224). This variant is also known as c.271G>A and p.Asp91Asn. ClinVar contains an entry for this variant (Variation ID: 135986). 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. Experimental studies have shown that this missense change does not substantially affect MUTYH function (PMID: 25820570, 26694661). 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. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 28, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jun 26, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 25, 2023	This missense variant replaces aspartic acid with asparagine at codon 105 of the MUTYH protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant protein (also known as p.Asp77Asn and p.Asp91Asn in the literature) exhibits similar DNA glycosylase activity and ability in mutation suppression compared to the wild-type protein (PMID: 25820570, 26694661). This variant has been detected in heterozygosity without a known second mutation in at least one individual affected with colorectal cancer and polyposis (PMID: 16140997, 16408224). This variant has also been identified in 9/282862 chromosomes 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. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 09, 2020	proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.55

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.52

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.6

D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.36

Sift

Benign

0.058

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

Sift4G

Uncertain

0.032

D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

0.65, 0.93, 0.80

.;.;.;.;.;P;P;.;P;.;.;.

Vest4

0.65

MVP

0.94

MPC

0.13

ClinPred

0.81

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.44

gMVP

0.47

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over