rs587780748

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_001048174.2(MUTYH):c.523C>T(p.Arg175Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R175G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 0.617

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-45332656-C-G is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.25840956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2 linkuse as main transcript	c.607C>T	p.Arg203Cys	missense_variant	8/16	ENST00000710952.2
MUTYH	NM_001048174.2 linkuse as main transcript	c.523C>T	p.Arg175Cys	missense_variant	8/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2 linkuse as main transcript	c.607C>T	p.Arg203Cys	missense_variant	8/16		NM_001128425.2
MUTYH	ENST00000456914.7 linkuse as main transcript	c.523C>T	p.Arg175Cys	missense_variant	8/16	1	NM_001048174.2	A1	Q9UIF7-6

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251456

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 22, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 203 of the MUTYH protein (p.Arg203Cys). This variant is present in population databases (rs587780748, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer or multiple colorectal adenomas (PMID: 17949294, 27978560, 28135145). This variant is also known as c.565C>T (p.Arg189Cys). ClinVar contains an entry for this variant (Variation ID: 135988). 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. 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	Baylor Genetics	Oct 19, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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 203 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with polyposis or colorectal cancer (PMID: 17949294, 28135145, 27978560), melanoma, kidney cancer, uterine cancer, or breast cancer (PMID: 29684080). This variant has been identified in 12/282786 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 provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 30, 2023	In the published literature, this variant has been reported in individuals with suspected Lynch syndrome and/or polyposis (PMID: 28502729 (2017)), colorectal cancer and colonic adenomas (PMIDs: 27978560 (2017), 28135145 (2017), 17949294 (2007)), and kidney renal papillary cell carcinoma (PMID: 29684080 (2018)). In a breast cancer association study, this variant was not seen in individuals with cancer but was seen in healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). The frequency of this variant in the general population, 0.00014 (5/35430 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 benign or damaging. 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	Apr 16, 2022	Observed in individuals with a personal history of adenomatous polyps or colorectal cancer (Olschwang 2007, Yurgelun 2017, Pearlman 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.565C>T (p.Arg189Cys); This variant is associated with the following publications: (PMID: 17949294, 26944241, 28135145, 27978560, 28502729, 29596542, 33553733) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 15, 2022	This missense variant replaces arginine with cysteine at codon 203 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with polyposis or colorectal cancer (PMID: 17949294, 28135145, 27978560), melanoma, kidney cancer, uterine cancer, or breast cancer (PMID: 29684080). This variant has been identified in 12/282786 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	Nov 21, 2022	The p.R203C variant (also known as c.607C>T), located in coding exon 8 of the MUTYH gene, results from a C to T substitution at nucleotide position 607. The arginine at codon 203 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was previously reported in an individual with greater than 5 colorectal adenomas; however, no other alterations in the MUTYH gene were detected and this alteration was classified as a variant of unknown significance (Olschwang S et al. Genet. Test. 2007;11:315-20). This alteration has also been reported in 1/450 patients with colorectal cancer diagnosed under the age of 50 years who were tested with a multi-gene panel (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet., 2018 04;14:e1007352). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 20, 2022

Variant summary: MUTYH c.607C>T (p.Arg203Cys) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) 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 4.4e-05 in 251456 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.0046), allowing no conclusion about variant significance. The variant c.607C>T (aka. c.565C>T (p.Arg189Cys)) has been reported in the literature in individuals affected with colorectal cancer and polyps (Olschwang_2007, Rey_2017, Pearlman_2016, Yurgelun_2017). However, these reports 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 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Benign

-0.10

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.23

M_CAP

Benign

0.066

MetaRNN

Benign

0.26

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

MetaSVM

Uncertain

0.043

MutationTaster

Benign

0.89

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

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-4.5

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

REVEL

Uncertain

0.36

Sift

Benign

0.10

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

Sift4G

Benign

0.079

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

Polyphen

0.84, 0.69, 0.68

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

Vest4

0.40

MutPred

0.49

.;.;.;.;.;.;.;.;Gain of catalytic residue at M201 (P = 0);.;.;.;

MVP

0.93

MPC

0.25

ClinPred

0.24

GERP RS

3.6

Varity_R

0.36

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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