1-45329371-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting

The NM_001048174.2(MUTYH):c.1501C>A(p.Leu501Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000808 in 1,614,220 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L501L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0015 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00073 ( 18 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18O:1

Conservation

PhyloP100: 1.64

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 -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073990226).

BP6

Variant 1-45329371-G-T is Benign according to our data. Variant chr1-45329371-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 41756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00154 (234/152332) while in subpopulation AMR AF= 0.0136 (208/15310). AF 95% confidence interval is 0.0121. There are 2 homozygotes in gnomad4. There are 135 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.1501C>A	p.Leu501Met	missense_variant	Exon 16 of 16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MUTYH	ENST00000456914.7 link	c.1501C>A	p.Leu501Met	missense_variant	Exon 16 of 16	1	NM_001048174.2	ENSP00000407590.2	Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.*244C>A		non_coding_transcript_exon_variant	Exon 21 of 21			ENSP00000499896.1	A0A5F9ZGZ0
ENSG00000288208	ENST00000671898.1 link	n.*244C>A		3_prime_UTR_variant	Exon 21 of 21			ENSP00000499896.1	A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.00154

AC:

234

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0136

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:

0.0000588

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00346

AC:

870

AN:

251490

Hom.:

AF XY:

0.00252

AC XY:

343

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.0241

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.000732

AC:

1070

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000608

AC XY:

442

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0223

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.000695

GnomAD4 genome

AF:

0.00154

AC:

234

AN:

152332

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.0136

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000484

Hom.:

Bravo

AF:

0.00284

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00249

AC:

302

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:5

Jan 22, 2016

Vantari Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 07, 2018

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. -

Jul 09, 2024

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:4

Jul 29, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24728327, 21167187, 25820570, 22703879, 21153778, 28944238) -

Aug 17, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial adenomatous polyposis 2

Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified

Benign:2Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Dec 30, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 26, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of colon

Benign:2

Dec 15, 2014

Pathway Genomics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MUTYH p.Leu529Met variant was identified in the literature, although the frequency of this variant in an affected population was not provided. The variant was identified in dbSNP (rs3219496) as â€šÃ„Ãºwith other alleleâ€šÃ„Ã¹, ClinVar (classified as likely benign by Ambry Genetics, GeneDx, Pathway Genomics and 3 other submitters; and as benign by Invitae, Color, PreventionGenetics and 2 other submitters). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 893 of 282,882 chromosomes (16 homozygous) at a frequency of 0.003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 852 of 35,440 chromosomes (freq: 0.02), Other in 16 of 7226 chromosomes (freq: 0.002), African in 15 of 24,966 chromosomes (freq: 0.0006), East Asian in 3 of 19,954 chromosomes (freq: 0.0002), European in 6 of 129,186 chromosomes (freq: 0.00005), and South Asian in 1 of 30,616 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish or Finnish populations. Site-directed mutagenesis experiments demonstrated that the variant did not alter the functional activity of MUTYH in E. coli cells (Komine 2015). The p.Leu529 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Gastric cancer;C3272841:Familial adenomatous polyposis 2

Benign:1

Nov 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

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

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.82

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

MetaRNN

Benign

0.0074

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

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.6

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

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.64

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

REVEL

Benign

0.24

Sift

Benign

0.059

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

Sift4G

Benign

0.13

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

Polyphen

0.89, 0.94, 0.92

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

Vest4

0.47

MVP

0.81

MPC

0.37

ClinPred

0.021

GERP RS

4.4

Varity_R

0.16

gMVP

0.40

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