1-45332614-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1PP3

The NM_001128425.2(MUTYH):c.650G>A(p.Arg217His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,988 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R217S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

MUTYH
NM_001128425.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:14O:1

Conservation

PhyloP100: 2.56

Publications

8 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

MUTYH links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 45 uncertain in NM_001128425.2

PP3

MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001128425.2 link	c.650G>A	p.Arg217His	missense_variant	Exon 8 of 16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2 link	c.566G>A	p.Arg189His	missense_variant	Exon 8 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MUTYH	ENST00000710952.2 link	c.650G>A	p.Arg217His	missense_variant	Exon 8 of 16		NM_001128425.2	ENSP00000518552.2
MUTYH	ENST00000456914.7 link	c.566G>A	p.Arg189His	missense_variant	Exon 8 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1 link	n.1154G>A		non_coding_transcript_exon_variant	Exon 12 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251412

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1112008

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000920

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41414

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.000957

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000831

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Uncertain:6

Mar 22, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 30, 2023

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 histidine at codon 217 of the MUTYH protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in the compound heterozygous state in an individual affected with MUTYH-associated polyposis (PMID: 33130102). This variant has also been reported in an individual affected with colorectal adenomas (PMID 17949294), a family with familial colorectal cancer (however, the variant did not segregate with the disease; PMID 25307848), an individual with unspecified cancer (PMID: 26556299), individuals affected with breast cancer and healthy controls (PMID: 33471991). This variant has been identified in 11/282760 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. -

Dec 08, 2015

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. -

Jan 19, 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 histidine, which is basic and polar, at codon 217 of the MUTYH protein (p.Arg217His). This variant is present in population databases (rs147754007, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal adenomas and/or colorectal cancer (PMID: 17949294, 25307848, 33130102, 34326862, 35957908). ClinVar contains an entry for this variant (Variation ID: 140830). 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. -

Jul 02, 2018

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Jan 16, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R217H variant (also known as c.650G>A), located in coding exon 8 of the MUTYH gene, results from a G to A substitution at nucleotide position 650. The arginine at codon 217 is replaced by histidine, an amino acid with highly similar properties. This alteration, designated as p.Arg203His, has been reported as a variant of unknown significance in an adenomatous polyposis cohort (Olschwang S et al. Genet. Test. 2007;11:315-20). In a different study, this alteration was detected in a large Austrian kindred with familial colorectal cancer type X (FCCTX) in conjunction with a SEMA4A gene alteration; this alteration did not segregate with colorectal cancer in the family whereas the SEMA4A gene alteration did (Schulz E et al. Nat Commun. 2014 Oct 13;5:5191). In addition, this alteration was detected in the germline of an individual with advanced cancer who underwent tumor-normal sequencing; although clinical details were not provided, authors noted that the patient's phenotypic expression was not consistent with an autosomal recessive mode of inheritance (Schrader KA et al. JAMA Oncol. 2016 Jan;2(1):104-11). This amino acid position is 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. -

Dec 07, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

May 08, 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 histidine at codon 217 of the MUTYH protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in the compound heterozygous state in an individual affected with MUTYH-associated polyposis (PMID: 33130102). This variant has also been reported in an individual affected with colorectal adenomas (PMID 17949294), a family with familial colorectal cancer (however, the variant did not segregate with the disease; PMID 25307848), an individual with unspecified cancer (PMID: 26556299), individuals affected with breast cancer, and healthy controls (PMID: 33471991, 35980532; DOI: 10.3390/biomedicines11051386). This variant has been identified in 11/282760 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:2

Dec 19, 2022

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.650G>A (p.Arg217His) 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 3.9e-05 in 282760 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (3.9e-05 vs 0.0046), allowing no conclusion about variant significance. c.650G>A has been reported in the literature in at least one compound heterozygous individual affected with MUTYH-Associated Polyposis (Thomas_2021). It has also been observed in individuals with colorectal adenomas (e.g. Olschwang_2007 and Schulz_2014) and breast cancer (e.g. Dorling_2021, Pereira_2022, Guindalini_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters have assessed the variant since 2014: all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Nov 23, 2021

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the MUTYH gene demonstrated a sequence change, c.650G>A, in exon 8 that results in an amino acid change, p.Arg217His. This sequence change has been described in the gnomAD database with a frequency of 0.012% in the African/African American subpopulation (dbSNP rs147754007). The p.Arg217His change affects a highly conserved amino acid residue located in a domain of the MUTYH protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg217His substitution. This sequence change does not appear to have been previously described in individuals with MUTYH-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg217His change remains unknown at this time. ; -

not provided

Uncertain:2

Mar 20, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MUTYH c.650G>A (p.Arg217His) variant has been reported in the published literature in individuals affected with colorectal adenomas (PMID: 17949294 (2007)), MUTYH-associated polyposis (MAP) (PMID: 33130102 (2021)), familial colorectal cancer type X (FCCTX) (PMID: 25307848 (2014)), and breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH), 35264596 (2022)). This variant has also been identified in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). The frequency of this variant in the general population, 0.00012 (3/24934 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Oct 26, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with adenomatous polyps, colorectal cancer, and other cancers (Olschwang 2007, Schulz 2014, Schrader 2016); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.608G>A (p.Arg203His); This variant is associated with the following publications: (PMID: 17949294, 25307848, 26556299, 28873162) -

Carcinoma of colon

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MUTYH p.Arg217His variant was identified in APC-negative patients with more than 5 colorectal adenomas; the frequency of the variant in this cohort, zygosity and disease severity were not provided from this cohort (Olschwang 2007). It was also identified in a large Austrian kindred with Familial colorectal cancer type X (FCCTX), being studied for novel candidate gene mutations; but was excluded as the cause of neoplasms in this family due to non-segregation amongst family members (Schulz 2014). The variant was also identified in dbSNP (ID: rs147754007) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, Clinvitae database (classification uncertain significance), ClinVar database (classification uncertain significance by Ambry Genetics), UMD (2x with a â€šÃ„Ã¹unclassified variantâ€šÃ„Ã¹ classification), NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles (frequency: 0.0001) and in 1 of 4406 African American alleles (frequency: 0.0002), and the Exome Aggregation Consortium database (March 14, 2016) in 5 of 121252 chromosomes (freq. 0.00004) in the following populations: Latino in 1 of 11572 chromosomes (freq. 00009), South Asian in 1 of 16512 chromosomes (freq. 0.00006), European (Non-Finnish) in 3 of 66638 chromosomes (freq. 0.00005), but was not seen in African, East Asian, Finnish, and Other populations, increasing the likelihood this could be a low frequency benign variant. The p.Arg217 residue is conserved across mammals and lower organisms, and three out of four computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the His variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:-

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.38

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

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.77

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

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

3.1

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

PhyloP100

2.6

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.5

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

REVEL

Pathogenic

0.77

Sift

Benign

0.030

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

Sift4G

Benign

0.12

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

Polyphen

1.0

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

Vest4

0.58

MVP

0.98

MPC

0.59

ClinPred

0.95

GERP RS

3.5

PromoterAI

0.0042

Neutral

(source)

Varity_R

0.46

gMVP

0.57

Mutation Taster

=48/52

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over