1-45331833-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001048174.2(MUTYH):c.930G>C(p.Gln310His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,603,502 control chromosomes in the GnomAD database, including 56,797 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q310R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.27 ( 5852 hom., cov: 33)

Exomes 𝑓: 0.26 ( 50945 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:21O:1

Conservation

PhyloP100: -0.265

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:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0010225773).

BP6

Variant 1-45331833-C-G is Benign according to our data. Variant chr1-45331833-C-G is described in ClinVar as [Benign]. Clinvar id is 41767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45331833-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.930G>C	p.Gln310His	missense_variant	Exon 12 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.930G>C	p.Gln310His	missense_variant	Exon 12 of 16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.1518G>C		non_coding_transcript_exon_variant	Exon 16 of 21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.269

AC:

40958

AN:

152016

Hom.:

5824

Cov.:

show subpopulations

Gnomad AFR

AF:

0.264

Gnomad AMI

AF:

0.274

Gnomad AMR

AF:

0.400

Gnomad ASJ

AF:

0.262

Gnomad EAS

AF:

0.412

Gnomad SAS

AF:

0.238

Gnomad FIN

AF:

0.215

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.243

Gnomad OTH

AF:

0.297

GnomAD3 exomes

AF:

0.290

AC:

67377

AN:

232316

Hom.:

10651

AF XY:

0.277

AC XY:

34951

AN XY:

126078

show subpopulations

Gnomad AFR exome

AF:

0.263

Gnomad AMR exome

AF:

0.488

Gnomad ASJ exome

AF:

0.263

Gnomad EAS exome

AF:

0.397

Gnomad SAS exome

AF:

0.237

Gnomad FIN exome

AF:

0.220

Gnomad NFE exome

AF:

0.244

Gnomad OTH exome

AF:

0.288

GnomAD4 exome

AF:

0.260

AC:

377531

AN:

1451368

Hom.:

50945

Cov.:

AF XY:

0.257

AC XY:

185520

AN XY:

721162

show subpopulations

Gnomad4 AFR exome

AF:

0.266

Gnomad4 AMR exome

AF:

0.477

Gnomad4 ASJ exome

AF:

0.261

Gnomad4 EAS exome

AF:

0.420

Gnomad4 SAS exome

AF:

0.233

Gnomad4 FIN exome

AF:

0.228

Gnomad4 NFE exome

AF:

0.249

Gnomad4 OTH exome

AF:

0.270

GnomAD4 genome

AF:

0.270

AC:

41017

AN:

152134

Hom.:

5852

Cov.:

AF XY:

0.270

AC XY:

20054

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.263

Gnomad4 AMR

AF:

0.401

Gnomad4 ASJ

AF:

0.262

Gnomad4 EAS

AF:

0.412

Gnomad4 SAS

AF:

0.238

Gnomad4 FIN

AF:

0.215

Gnomad4 NFE

AF:

0.243

Gnomad4 OTH

AF:

0.305

Alfa

AF:

0.250

Hom.:

1622

Bravo

AF:

0.287

TwinsUK

AF:

0.249

AC:

922

ALSPAC

AF:

0.255

AC:

981

ESP6500AA

AF:

0.264

AC:

1161

ESP6500EA

AF:

0.249

AC:

2143

ExAC

AF:

0.268

AC:

32463

Asia WGS

AF:

0.359

AC:

1247

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:21Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8Other:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

May 12, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser372Phe in exon 12 of MUTYH: This variant is not expected to have clinical s ignificance because it has been identified in 49% (15851/32596) of Latino chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP rs3219489). -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 12, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:4

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23108399, 22703879, 22780951, 22926731, 18422726, 20149637, 22466227, 18823566, 19161591, 23499241, 23460202, 24728327, 18534194, 26377631, 25820570, 27153395, 29954149, 28628107, 27705013, 31027119, 30564557, 23618615, 31104418) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial adenomatous polyposis 2

Benign:4

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Dec 21, 2021

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 28, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Mar 27, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial multiple polyposis syndrome

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Gln338His variant was not identified in the literature. The p.Gln338 residue is not conserved in mammals and this variant is listed in dbSNP as a common polymorphism in different populations of origin with an average heterozygosity reported as 0.403+/-0.198 (dbSNP#: rs3219489), increasing the likelihood that the variant has no clinical significance. In summary, based on the above information, this variant is classified as benign. -

Carcinoma of colon

Benign:1

Jul 24, 2014

Pathway Genomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.086

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

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.44

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

MetaRNN

Benign

0.0010

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

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.7

.;.;.;.;.;M;.;.;.;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.0

N;N;N;N;N;N;N;N;N;.;N

REVEL

Benign

0.043

Sift

Benign

0.17

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

Sift4G

Benign

0.12

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

Polyphen

0.65, 0.33, 0.34

.;.;.;.;.;P;B;.;B;.;.

Vest4

0.13

MutPred

0.12

.;.;.;.;.;.;.;.;Loss of sheet (P = 0.0457);.;.;

MPC

0.13

ClinPred

0.016

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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