chr1-45331238-G-A

Position:

chr1-45331238-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001048174.2(MUTYH):c.1336C>T(p.Arg446Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000533 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R446H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:13

Conservation

PhyloP100: 6.83

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.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2 linkuse as main transcript	c.1420C>T	p.Arg474Cys	missense_variant	14/16	ENST00000710952.2
MUTYH	NM_001048174.2 linkuse as main transcript	c.1336C>T	p.Arg446Cys	missense_variant	14/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2 linkuse as main transcript	c.1420C>T	p.Arg474Cys	missense_variant	14/16		NM_001128425.2
MUTYH	ENST00000456914.7 linkuse as main transcript	c.1336C>T	p.Arg446Cys	missense_variant	14/16	1	NM_001048174.2	A1	Q9UIF7-6

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152224

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251490

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135922

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000547

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000665

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74364

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 10, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces arginine with cysteine at codon 474 of the MUTYH protein. This variant is also known as c.1378C>T (p.Arg460Cys) based on an alternative transcript (NM_001048171). 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 been reported in individuals affected with colorectal cancer (PMID: 28135145, 35668106), bilateral breast cancer (PMID: 32854451) and pancreatic cancer (PMID: 30836094). This variant has also been identified in 14/282888 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	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 474 of the MUTYH protein (p.Arg474Cys). This variant is present in population databases (rs200229669, gnomAD 0.009%). This missense change has been observed in individual(s) with bilateral breast cancer and colorectal cancer (PMID: 28135145, 32854451). This variant is also known as c.1378C>T (p.Arg460Cys). ClinVar contains an entry for this variant (Variation ID: 41754). 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 disruptive. 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. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 12, 2023	In the published literature, this variant has been reported in individuals with colorectal cancer (PMID: 28135145 (2017), 28944238 (2017), 35668106 (2022)), and breast cancer (PMID: 32854451 (2020), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). This variant has also been reported in unaffected individuals (PMID: 30267214 (2018), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). The frequency of this variant in the general population, 0.00026 (3/11610 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2024	Observed in individuals with colorectal cancer and breast cancer, and also in unaffected controls (PMID: 28135145, 32854451, 35668106, 30267214, 28944238, 33471991); 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; This variant is associated with the following publications: (PMID: 22722201, 22703879, 32854451, 28135145, 35668106, 30267214, 28944238, 33471991, 30836094, 27600092, 23108399) -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 02, 2023	This missense variant replaces arginine with cysteine at codon 474 of the MUTYH protein. This variant is also known as c.1378C>T (p.Arg460Cys) based on an alternative transcript (NM_001048171). 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 been reported in individuals affected with colorectal cancer (PMID: 28135145, 35668106), bilateral breast cancer (PMID: 32854451) and pancreatic cancer (PMID: 30836094). This variant has also been identified in 14/282888 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	Ambry Genetics	Sep 07, 2022	The p.R474C variant (also known as c.1420C>T), located in coding exon 14 of the MUTYH gene, results from a C to T substitution at nucleotide position 1420. The arginine at codon 474 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in 1/572 cancer-free atherosclerosis patients (Johnston JJ et al. Am. J. Hum. Genet. 2012 Jul;91:97-108). In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in two control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This variant was also reported in a cohort study of colorectal patients that also included a control group (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This variant was identified in the germline along with MUTYH c.603G>T (p.M201I) in a patient in the 80-89 year old age group with colorectal cancer (Georgeson P et al. Nat Commun, 2022 06;13:3254). In a multi-gene panel study of patients with bilateral breast cancer, this variant was observed in 1/139 cases (Fanale D et al. Cancers (Basel), 2020 Aug;12:). This amino acid position is well conserved in available vertebrate species. In addition, this alteration 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Mar 12, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 03, 2020

Variant summary: MUTYH c.1420C>T (p.Arg474Cys) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) and C-terminal domain (IPR029119) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251490 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (5.2e-05 vs 0.0046), allowing no conclusion about variant significance. c.1420C>T has been reported in the literature in individuals affected with atherosclerosis, colorectal cancer and pancreatic ductal adenocarcinoma (Johnston_2012, Yurgelun_2017, Singhi_2019). These reports however, do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Carcinoma of colon

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

Neoplasm of stomach;C0206711:Pilomatrixoma;C3272841:Familial adenomatous polyposis 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

.;.;.;.;.;.;D;.;.;.;.;D

Eigen

Benign

0.049

Eigen_PC

Benign

0.036

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;.;D;.;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.85

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

MetaSVM

Uncertain

-0.042

MutationAssessor

Uncertain

2.6

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-4.8

D;D;D;D;D;D;D;D;D;D;D;.

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;.

Sift4G

Pathogenic

0.0010

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

Polyphen

0.11, 0.84, 0.59

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

Vest4

0.88

MVP

0.82

MPC

0.32

ClinPred

0.81

GERP RS

4.3

Varity_R

0.48

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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