chr1-45332768-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_001048174.2(MUTYH):​c.487C>T​(p.Arg163Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R163Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

3
10
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12O:1

Conservation

PhyloP100: 3.89

Publications

11 publications found
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 Gene-Disease associations (from GenCC):
  • familial adenomatous polyposis 2
    Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
  • colorectal cancer
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
  • familial ovarian cancer
    Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
  • hereditary breast carcinoma
    Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_001048174.2

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MUTYHNM_001048174.2 linkc.487C>T p.Arg163Trp missense_variant Exon 7 of 16 ENST00000456914.7 NP_001041639.1 Q9UIF7-6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MUTYHENST00000456914.7 linkc.487C>T p.Arg163Trp missense_variant Exon 7 of 16 1 NM_001048174.2 ENSP00000407590.2 Q9UIF7-6
ENSG00000288208ENST00000671898.1 linkn.1075C>T non_coding_transcript_exon_variant Exon 11 of 21 ENSP00000499896.1 A0A5F9ZGZ0

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152082
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000119
AC:
3
AN:
251480
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000280
AC:
41
AN:
1461880
Hom.:
0
Cov.:
36
AF XY:
0.0000248
AC XY:
18
AN XY:
727242
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.0000224
AC:
1
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000333
AC:
37
AN:
1112006
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152082
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74288
show subpopulations
African (AFR)
AF:
0.0000724
AC:
3
AN:
41412
American (AMR)
AF:
0.00
AC:
0
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68000
Other (OTH)
AF:
0.00
AC:
0
AN:
2086
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:6Other:1
Sep 13, 2023
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
GenomeConnect - Invitae Patient Insights Network
Significance:not provided
Review Status:no classification provided
Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 06-18-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Feb 05, 2024
All of Us Research Program, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces arginine with tryptophan at codon 191 of the MUTYH protein. This variant is also known as NM_001048171.1:c.529C>T (p.Arg177Trp) in the literature. 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: 18294051) or breast cancer (PMID: 31742824, 33471991). In a large international case-control meta-analysis, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 3/251480 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. -

Jan 14, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 191 of the MUTYH protein (p.Arg191Trp). This variant is present in population databases (rs761101420, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer and/or personal or family history of hereditary breast and ovarian cancer (PMID: 18294051, 31742824). This variant is also known as p.Arg177Trp. ClinVar contains an entry for this variant (Variation ID: 186056). 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. -

Dec 23, 2021
MGZ Medical Genetics Center
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 05, 2024
Molecular Pathology, Peter Maccallum Cancer Centre
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 22, 2018
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Hereditary cancer-predisposing syndrome Uncertain:3
Jun 24, 2021
Sema4, Sema4
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:curation

- -

Jan 08, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.R191W variant (also known as c.571C>T), located in coding exon 7 of the MUTYH gene, results from a C to T substitution at nucleotide position 571. The arginine at codon 191 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration, designated as p.Arg177Trp, was detected in a Spanish patient diagnosed at age 29 with left-sided colon cancer but with no associated polyps (Riegert-Johnson DL et al. Genet Test, 2007;11:361-5). This alteration was also identified in a cohort of 882 Chinese individuals who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci., 2020 Feb;111:647-657). 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. -

Apr 24, 2023
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces arginine with tryptophan at codon 191 of the MUTYH protein. This variant is also known as NM_001048171.1:c.529C>T (p.Arg177Trp) in the literature. 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: 18294051) or breast cancer (PMID: 31742824, 33471991). In a large international case-control meta-analysis, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 3/251480 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 specified Uncertain:1
Nov 27, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: MUTYH c.571C>T (p.Arg191Trp) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251480 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.571C>T has been reported in the literature in heterozygous individuals affected with colorectal cancer without associated polyps, cardiac dysfunction, and increased risk of hereditary breast and ovarian cancer (e.g. Riegert-Johnson_2007, Lam_2015, Shao_2020). 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. The following publications have been ascertained in the context of this evaluation (PMID: 28491533, 18294051, 31742824). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Gastric cancer;C3272841:Familial adenomatous polyposis 2 Uncertain:1
Nov 09, 2020
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:1
May 28, 2025
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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; Also known as c.529C>T (p.R177W); This variant is associated with the following publications: (PMID: 18294051, 33471991, 28491533, 31742824) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.095
BayesDel_addAF
Benign
-0.0019
T
BayesDel_noAF
Uncertain
-0.060
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
.;.;.;.;.;D;.;.;.;T;.;T
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.20
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
.;D;.;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Uncertain
0.47
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.20
D
MutationAssessor
Uncertain
2.5
.;.;.;.;.;M;.;.;.;.;.;.
PhyloP100
3.9
PrimateAI
Benign
0.35
T
PROVEAN
Uncertain
-3.8
D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Uncertain
0.64
Sift
Uncertain
0.0060
D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.019
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;.;.;D;D;.;D;.;.;.
Vest4
0.64
MutPred
0.51
.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0055);.;.;.;
MVP
0.95
MPC
0.55
ClinPred
0.93
D
GERP RS
3.0
PromoterAI
0.0034
Neutral
Varity_R
0.67
gMVP
0.55
Mutation Taster
=70/30
polymorphism

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

Other links and lift over

dbSNP: rs761101420; hg19: chr1-45798440; COSMIC: COSV58343896; COSMIC: COSV58343896; API