chr1-45331433-C-T

Position:

chr1-45331433-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_001048174.2(MUTYH):c.1226G>A(p.Arg409Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 0.109

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 Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08544466).

BP6

Variant 1-45331433-C-T is Benign according to our data. Variant chr1-45331433-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141933.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}. Variant chr1-45331433-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2 linkuse as main transcript	c.1310G>A	p.Arg437Gln	missense_variant	13/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2 linkuse as main transcript	c.1226G>A	p.Arg409Gln	missense_variant	13/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2 linkuse as main transcript	c.1310G>A	p.Arg437Gln	missense_variant	13/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7 linkuse as main transcript	c.1226G>A	p.Arg409Gln	missense_variant	13/16	1	NM_001048174.2	ENSP00000407590	A1	Q9UIF7-6

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152196

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251368

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135868

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

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:

0.000188

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 437 of the MUTYH protein (p.Arg437Gln). This variant is present in population databases (rs587782120, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and/or colorectal cancer (CRC) (PMID: 15943555, 35264596). This variant is also known as c.1268G>A. ClinVar contains an entry for this variant (Variation ID: 141933). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect MUTYH function (PMID: 25820570). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 31, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 04, 2018	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	Jan 24, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 03, 2017	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 26, 2022

Variant summary: MUTYH c.1310G>A (p.Arg437Gln) results in a conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-06 in 254566 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1310G>A has been reported in the literature in individuals affected with sporadic colorectal cancer (example, Zhou_2005). This report does not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. At least one publication reports experimental evidence evaluating an impact on protein function (example, Komine_2015). These results showed no damaging effect of this variant in an assay evaluating functional complementation in a MutY-disrupted E Coli strain. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=6) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 10, 2018

This variant is denoted MUTYH c.1310G>A at the cDNA level, p.Arg437Gln (R437Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant, also published as MUTYH Arg423Gln (R423Q) using alternate nomenclature, has been observed in at least three individuals with sporadic colorectal cancer (Zhou 2005). An E. coli-based complementation assay found that MUTYH Arg437Gln exhibited a spontaneous mutation rate similar to wild-type controls, suggesting that this variant retains protein function (Komine 2015). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). MUTYH Arg437Gln is located in the NUDIX domain (Ruggieri 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MUTYH Arg437Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.? -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Benign

-0.30

CADD

Benign

4.0

DANN

Benign

0.72

DEOGEN2

Benign

0.15

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

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.83

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

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.085

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

MetaSVM

Benign

-0.67

MutationAssessor

Benign

-1.1

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.10

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

REVEL

Uncertain

0.33

Sift

Benign

0.89

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

Sift4G

Benign

0.86

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

Polyphen

0.0010, 0.0020

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

Vest4

0.15

MVP

0.74

MPC

0.13

ClinPred

0.020

GERP RS

-2.8

Varity_R

0.035

gMVP

0.18

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